Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them

ABSTRACT

The present invention relates to bicyclic heterocyclic groups of general formula  
                 
 
     wherein  
     R a , R b , R c , R d  and X are defined as in claim 1, the tautomers, the stereoisomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids which have valuable pharmacological properties, particularly an inhibitory effect on signal transduction mediated by tyrosine kinases, the use thereof for treating diseases, particularly tumoral diseases, as well as benign prostate hyperplasia (BPH), diseases of the lungs and respiratory tract, and the preparation thereof.

RELATED APPLICATIONS

[0001] Benefit of U.S. Provisional Application Serial No. 60/381,176filed on May 16, 2002 is hereby claimed, and said Application is hereinincorporated by reference.

FIELD OF INVENTION

[0002] This invention relates to bicyclic heterocyclic compounds activeas inhibitors of signal transduction mediated by tyrosine kinases. Theinvention also relates to processes for preparing such compounds andpharmaceutical compositions comprising them.

BACKGROUND OF THE INVENTION

[0003] Inhibitors of signal transduction mediated by tyrosine kinasesuseful in the treatment of tumoral diseases as well as benign prostatehyperplasia (BPH) diseases of the lungs and respiratory tract. Tyrosinekinase inhibitors have been reported for the treatment ofhyper-secretory respitory diseases. WO 00/10588.

SUMMARY AND DESCRIPTION OF THE INVENTION

[0004] The present invention relates to bicyclic heterocyclic groups ofgeneral formula

[0005] the tautomers, the stereoisomers, the mixtures and the saltsthereof, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases which have valuable pharmacologicalproperties, particularly an inhibitory effect on signal transductionmediated by tyrosine kinases, the use thereof for treating diseases,particularly tumoral diseases, as well as benign prostate hyperplasia(BPH), diseases of the lungs and respiratory tract, and the preparationthereof.

[0006] In the above general formula I

[0007] R^(a) denotes a hydrogen atom or a C₁₋₄-alkyl group,

[0008] R^(b) denotes a phenyl or 1-phenylethyl group, wherein the phenylnucleus is substituted in each case by the groups R¹ to R³, while

[0009] R¹ and R², which may be identical or different, in each casedenote a hydrogen, fluorine, chlorine, bromine or iodine atom,

[0010] a C₁₋₄-alkyl, hydroxy, C₁₋₄-alkoxy, C₂₋₃-alkenyl or C₂₋₃-alkynylgroup,

[0011] an aryl, aryloxy, arylmethyl or arylmethoxy group,

[0012] a heteroaryl, heteroaryloxy, heteroarylmethyl orheteroarylmethoxy group,

[0013] a methyl or methoxy group substituted by 1 to 3 fluorine atoms or

[0014] a cyano, nitro or amino group, and

[0015] R³ denotes a hydrogen, fluorine, chlorine or bromine atom or

[0016] a methyl or trifluoromethyl group,

[0017] R^(c) denotes a cyclobutyl, cyclopentyl or cyclohexyl group whichis substituted in each case by a group R⁴—N—R⁵, while

[0018] R⁴ denotes a hydrogen atom or a C₁₋₃-alkyl group and

[0019] R⁵ denotes a hydrogen atom or a C₁₋₃-alkyl group,

[0020] an aminocarbonyl-C₁₋₃-alkyl, C₁₋₃-alkylaminocarbonyl-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)aminocarbonyl-C₁₋₃-alkyl,pyrrolidin-1-ylcarbonyl-C₁₋₃-alkyl, piperidin-1-ylcarbonyl-C₁₋₃-alkyl,homopiperidin-1-ylcarbonyl-C₁₋₃-alkyl, morpholin-4-ylcarbonyl-C₁₋₃-alkyl, homomorpholin-4-ylcarbonyl-C₁₋₃-alkyl,piperazin-1-ylcarbonyl-C₁₋₃-alkyl,4-C₁₋₃-alkyl-piperazin-1-ylcarbonyl-C₁₋₃-alkyl,homopiperazin-1-ylcarbonyl-C₁₋₃-alkyl or a4-C₁₋₃-alkyl-homopiperazin-1-ylcarbonyl-C₁₋₃-alkyl group,

[0021] a hydroxy-C₂₋₄-alkyl, C₁₋₃-alkyloxy-C₂₋₄-alkyl,C₁₋₄-alkyloxy-carbonylamino-C₂₋₄-alkyl, amino-C₂₋₄-alkyl,C₁₋₃-alkylamino-C₂₋₄-alkyl, di-(C₁₋₃-alkyl)amino-C₂₋₄-alkyl,C₁₋₃-alkylcarbonylamino-C₂₋₄-alkyl, aminocarbonylamino-C₂₋₄-alkyl,C₁₋₃-alkylaminocarbonylamino-C₂₋₄-alkyl,di-(C₁₋₃-alkyl)amino-carbonylamino-C₂₋₄-alkyl,pyrrolidin-1-ylcarbonylamino-C₂₋₄-alkyl,piperidin-1-ylcarbonylamino-C₂₋₄-alkyl,morpholin-4-ylcarbonylamino-C₂₋₄-alkyl, C₁₋₃-alkylsulphonyl-C₂₋₄-alkylor a C₁₋₃-alkylsulphonylamino-C₂₋₄-alkyl group,

[0022] a (2-oxo-pyrrolidin-1-yl)-C₂₋₄-alkyl,(2-oxopiperidin-1-yl)-C₂₋₄-alkyl, (3-oxo-morpholin-4-yl)-C₂₋₄-alkyl,(2-oxo-imidazolidin-1-yl)-C₂₋₄-alkyl,(2-oxo-3-C₁₋₃-alkyl-imidazolidin-1-yl)-C₂₋₄-alkyl,(2-oxo-hexahydropyrimidin-1-yl)-C₂₋₄-alkyl or a(2-oxo-3-C₁₋₃-alkyl-hexahydropyrimidin-1-yl)-C₂₋₄-alkyl group,

[0023] a C₁₋₄-alkylsulphonyl, chloro-C₁₋₄-alkylsulphonyl,bromo-C₁₋₄-alkylsulphonyl, amino-C₁₋₄-alkylsulphonyl,C₁₋₃-alkylamino-C₁₋₄-alkylsulphonyl,di-(C₁₋₃-alkyl)amino-C₁₋₄-alkylsulphonyl,(pyrrolidin-1-yl)-C₁₋₄-alkylsulphonyl,(piperidin-1-yl)-C₁₋₄-alkylsulphonyl,(homopiperidin-1-yl)-C₁₋₄-alkylsulphonyl,(morpholin-4-yl)-C₁₋₄-alkylsulphonyl,(homomorpholin-4-yl)-C₁₋₄-alkylsulphonyl,(piperazin-1-yl)-C₁₋₄-alkylsulphonyl,(4-C₁₋₃-alkyl-piperazin-1-yl)-C₁₋₄-alkylsulphonyl,(homopiperazin-1-yl)-C₁₋₄-alkylsulphonyl or a(4-C₁₋₃-alkyl-homopiperazin-1-yl)-C₁₋₄-alkylsulphonyl group,

[0024] a C₁₋₄-alkyloxycarbonyl group,

[0025] a formyl, C₁₋₄-alkyl-carbonyl, C₁₋₃-alkyloxy-C₁₋₄-alkyl-carbonyl,tetrahydrofuranylcarbonyl, tetrahydropyranylcarbonyl,amino-C₁₋₄-alkyl-carbonyl, C₁₋₃-alkylamino-C₁₋₄-alkyl-carbonyl,di-(C₁₋₃-alkyl)amino-C₁₋₄-alkyl-carbonyl,pyrrolidin-1-yl-C₁₋₄-alkyl-carbonyl, piperidin-1-yl-C₁₋₄-alkyl-carbonyl,(homopiperidin-1-yl)-C₁₋₄-alkyl-carbonyl,morpholin-4-yl-C₁₋₄-alkyl-carbonyl,(homomorpholin-4-yl)-C₁₋₄-alkyl-carbonyl,(piperazin-1-yl)-C₁₋₄-alkyl-carbonyl,(4-C₁₋₃-alkyl-piperazin-1-yl)-C₁₋₄-alkyl-carbonyl,(homo-piperazin-1-yl)-C₁₋₄-alkyl-carbonyl,(4-C₁₋₃-alkyl-homopiperazin-1-yl)-C₁₋₄-alkyl-carbonyl or aC₁₋₃-alkylsulphonyl-C₁₋₄-alkyl-carbonyl group,

[0026] a cyano, aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,di-(C₁₋₃-alkyl)amino-carbonyl, (C₁₋₃-alkyloxy-C₂₋₄-alkyl)aminocarbonyl,N-(C₁₋₃-alkyl)-N-(C₁₋₃-alkyloxy-C₂₋₄-alkyl)aminocarbonyl,arylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,homopiperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl,3-oxa-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl,8-oxa-3-aza-[3.2.1]oct-3-ylcarbonyl, piperazin-1-ylcarbonyl,4-C₁₋₃-alkyl-piperazin-1-ylcarbonyl, homopiperazin-1-ylcarbonyl,4-C₁₋₃-alkyl-homopiperazin-1-ylcarbonyl, aminosulphonyl,C₁₋₃-alkyl-aminosulphonyl, di-(C₁₋₃-alkyl)amino-sulphonyl,pyrrolidin-1-yl-sulphonyl, piperidin-1-ylsulphonyl,homopiperidin-1-ylsulphonyl, morpholin-4-ylsulphonyl,homomorpholin-4-ylsulphonyl, piperazin-1-ylsulphonyl,4-C₁₋₃-alkyl-piperazin-1-ylsulphonyl, homopiperazin-1-ylsulphonyl or a4-C₁₋₃-alkyl-homopiperazin-1-ylsulphonyl group,

[0027] a cyclobutyl, cyclopentyl or cyclohexyl group which issubstituted in each case by a group R⁶, where

[0028] R⁶ denotes a 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl,3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl,2-oxo-3-C₁₋₃-alkyl-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl or a2-oxo-3-C₁₋₃-alkyl-hexahydropyrimidin-1-yl group,

[0029] an azetidin-3-yl group which is substituted in the 1 position bythe group R⁵, while R⁵ is as hereinbefore defined,

[0030] a pyrrolidin-3-yl group which is substituted in the 1 position bythe group R⁵, while R⁵ is as hereinbefore defined,

[0031] a piperidin-3-yl group which is substituted in the 1 position bythe group R⁵, while R⁵ is as hereinbefore defined,

[0032] a piperidin-4-yl group which is substituted in the 1 position bythe group R⁵, while R⁵ is as hereinbefore defined,

[0033] or a tetrahydrofuran-3-yl, tetrahydropyran-3-yl ortetrahydropyran-4-yl group,

[0034] R^(d) denotes a hydrogen atom or a fluorine, chlorine or bromineatom, a hydroxy group,

[0035] a C₁₋₄-alkyloxy group,

[0036] a methoxy group substituted by 1 to 3 fluorine atoms,

[0037] an ethyloxy group substituted by 1 to 5 fluorine atoms,

[0038] a C₂₋₄-alkyloxy group which is substituted by a group R⁶ or R⁷,while

[0039] R⁶ is as hereinbefore defined and

[0040] R⁷ denotes a hydroxy, C₁₋₃-alkyloxy, C₃₋₆-cycloalkyloxy, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino, bis-(2-methoxyethyl)-amino,pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl,homomorpholin-4-yl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl,3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl,piperazin-1-yl, 4-C₁₋₃-alkyl-piperazin-1-yl, homopiperazin-1-yl orC₁₋₃-alkyl-homopiperazin-1-yl group, or

[0041] a formylamino, C₁₋₄-alkylcarbonylamino,C₁₋₃-alkyloxy-C₁₋₃-alkyl-carbonylamino, C₁₋₄-alkyloxycarbonylamino,aminocarbonylamino, C₁₋₃-alkylaminocarbonylamino,di-(C₁₋₃-alkyl)aminocarbonylamino, pyrrolidin-1-ylcarbonylamino,piperidin-1-ylcarbonylamino, piperazin-1-ylcarbonylamino,4-C₁₋₃-alkyl-piperazin-1-ylcarbonylamino, morpholin-4-ylcarbonylamino ora C₁₋₄-alkylsulphonylamino group,

[0042] a C₃₋₇-cycloalkyloxy or C₃₋₇-cycloalkyl-C₁₋₄-alkyloxy group,

[0043] a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy ortetrahydropyran-4-yloxy group,

[0044] a tetrahydrofuranyl-C₁₋₄-alkyloxy ortetrahydropyranyl-C₁₋₄-alkyloxy group,

[0045] a C₁₋₄-alkoxy group which is substituted by a pyrrolidinyl,piperidinyl or homopiperidinyl group substituted in the 1 position bythe group R⁸, while

[0046] R⁸ denotes a hydrogen atom or a C₁₋₃-alkyl group,

[0047] or a C₁₋₄-alkoxy group which is substituted by a morpholinylgroup substituted in the 4 position by the group R⁸, while R⁸ is ashereinbefore defined, and

[0048] X denotes a methyne group substituted by a cyano group or anitrogen atom, and

[0049] by the aryl groups mentioned in the definition of the abovegroups is meant in each case a phenyl group which is mono- ordisubstituted by R⁹, while the substituents may be identical ordifferent and

[0050] R⁹ denotes a hydrogen atom, a fluorine, chlorine, bromine oriodine atom or a C₁₋₃-alkyl, hydroxy, C₁₋₃-alkyloxy, difluoromethyl,trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyano group,

[0051] by the heteroaryl groups mentioned in the definition of the abovegroups is meant a pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group,while the abovementioned heteroaryl groups are each mono- ordisubstituted by the group R⁹, while the substituents may be identicalor different and R⁹ is as hereinbefore defined, and

[0052] the abovementioned pyrrolidinyl, piperidinyl, piperazinyl andmorpholinyl groups may be substituted in each case by one or twoC₁₋₃-alkyl groups, and

[0053] unless otherwise stated, the abovementioned alkyl groups may bestraight-chained or branched,

[0054] with the proviso that the compound4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazolineis excluded.

[0055] Preferred compounds of the above general formula I are thosewherein

[0056] R^(a) denotes a hydrogen atom,

[0057] R^(b) denotes a phenyl group substituted by the groups R¹ to R³,while

[0058] R¹ denotes a hydrogen, fluorine, chlorine or bromine atom,

[0059] a methyl, trifluoromethyl or ethynyl group,

[0060] a phenyloxy or phenylmethoxy group, while the phenyl moiety ofthe abovementioned groups is optionally substituted by a fluorine orchlorine atom, or

[0061] a pyridyloxy or pyridinylmethoxy group, while the pyridinylmoiety of the abovementioned groups is optionally substituted by amethyl or trifluoromethyl group,

[0062] R² denotes a hydrogen, fluorine or chlorine atom or a methylgroup and

[0063] R³ denotes a hydrogen atom,

[0064] R^(c) denotes a cyclopentyl group which is substituted in the 3position by a group R⁴—N—R⁵, while

[0065] R⁴ denotes a hydrogen atom or a C₁₋₃-alkyl group and

[0066] R⁵ denotes a hydrogen atom or a C₁₋₃-alkyl group,

[0067] an aminocarbonyl-C₁₋₃-alkyl, C₁₋₃-alkylaminocarbonyl-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)aminocarbonyl-C₁₋₃-alkyl,pyrrolidin-1-ylcarbonyl-C₁₋₃-alkyl, piperidin-1-ylcarbonyl-C₁₋₃-alkyl,piperazin-1-ylcarbonyl-C₁₋₃-alkyl,4-C₁₋₃-alkyl-piperazin-1-yl-carbonyl-C₁₋₃-alkyl ormorpholin-4-ylcarbonyl-C₁₋₃-alkyl group,

[0068] a hydroxy-C₂₋₄-alkyl, C₁₋₃-alkyloxy-C₂₋₄-alkyl,C₁₋₄-alkyloxy-carbonylamino-C₂₋₄-alkyl, amino-C₂₋₄-alkyl,C₁₋₃-alkylamino-C₂₋₄-alkyl, di-(C₁₋₃-alkyl)amino-C₂₋₄-alkyl,C₁₋₃-alkylcarbonylamino-C₂₋₄-alkyl, aminocarbonylamino-C₂₋₄-alkyl,C₁₋₃-alkylaminocarbonylamino-C₂₋₄-alkyl,di-(C₁₋₃-alkyl)amino-carbonylamino-C₂₋₄-alkyl,morpholin-4-ylcarbonylamino-C₂₋₄-alkyl, C₁₋₃-alkylsulphonyl-C₂₋₄-alkylor C₁₋₃-alkylsulphonylamino-C₂₋₄-alkyl group,

[0069] a (2-oxo-pyrrolidin-1-yl)-C₂₋₄-alkyl,(2-oxopiperidin-1-yl)-C₂₋₄-alkyl, (3-oxo-morpholin-4-yl)-C₂₋₄-alkyl,(2-oxo-imidazolidin-1-yl)-C₂₋₄-alkyl,(2-oxo-3-methyl-imidazolidin-1-yl)-C₂₋₄-alkyl,(2-oxo-hexahydropyrimidin-1-yl)-C₂₋₄-alkyl or(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-C₂₋₄-alkyl group,

[0070] a C₁₋₃-alkylsulphonyl, chloro-C₂₋₄-alkylsulphonyl,bromo-C₂₋₄-alkylsulphonyl, amino-C₂₋₄-alkylsulphonyl,C₁₋₃-alkylamino-C₂₋₄-alkylsulphonyl,di-(C₁₋₃-alkyl)amino-C₂₋₄-alkylsulphonyl,(pyrrolidin-1-yl)-C₂₋₄-alkylsulphonyl,(piperidin-1-yl)-C₂₋₄-alkylsulphonyl or(morpholin-4-yl)-C₂₋₄-alkylsulphonyl group,

[0071] a C₁₋₄-alkyloxy-carbonyl group,

[0072] a formyl, C₁₋₃-alkyl-carbonyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl-carbonyl,tetrahydrofuranylcarbonyl, tetrahydropyranylcarbonyl,amino-C₁₋₃-alkyl-carbonyl, C₁₋₃-alkylamino-C₁₋₃-alkyl-carbonyl,di-(C₁₋₃-alkyl)amino-C₁₋₃-alkyl-carbonyl,pyrrolidin-1-yl-C₁₋₃-alkyl-carbonyl, piperidin-1-yl-C₁₋₃-alkyl-carbonyl,piperazin-1-yl-C₁₋₃-alkyl-carbonyl,4-C₁₋₃-alkyl-piperazin-1-yl-C₁₋₃-alkyl-carbonyl,morpholin-4-yl-C₁₋₃-alkyl-carbonyl or aC₁₋₃-alkylsulphonyl-C₁₋₃-alkyl-carbonyl group,

[0073] a cyano, aminocarbonyl, C₁₋₃-alkyl-aminocarbonyl,di-(C₁₋₃-alkyl)amino-carbonyl, (C₁₋₃-alkyloxy-C₂₋₄-alkyl)aminocarbonyl,N-(C₁₋₃-alkyl)-N-(C₁₋₃-alkyloxy-C₂₋₄-alkyl)aminocarbonyl,phenylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,morpholin-4-ylcarbonyl, C₁₋₃-alkyl-morpholin-4-ylcarbonyl,di-(C₁₋₃-alkyl)morpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl,2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl,3-oxa-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl,8-oxa-3-aza-bicyclo[3.2.1]oct-3-ylcarbonyl, piperazin-1-ylcarbonyl,4-(C₁₋₃-alkyl)-piperazin-1-ylcarbonyl, aminosulphonyl,C₁₋₃-alkyl-aminosulphonyl, di-(C₁₋₃-alkyl)amino-sulphonyl,pyrrolidin-1-yl-sulphonyl, piperidin-1-ylsulphonyl or amorpholin-4-ylsulphonyl group, or

[0074] a cyclopentyl group which is substituted in the 3 position by agroup R⁶, while

[0075] R⁶ denotes a 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl,3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl,2-oxo-3-methyl-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl or a2-oxo-3-methyl-hexahydropyrimidin-1-yl group,

[0076] a cyclohexyl group which is substituted in the 3 position or inthe 4 position by a group R⁴—N—R⁵, while R⁴ and R⁵ are as hereinbeforedefined,

[0077] a cyclohexyl group which is substituted in the 3 position or inthe 4 position by a group R⁶, while R⁶ is as hereinbefore defined,

[0078] a pyrrolidin-3-yl group which is substituted in the 1 position bythe group R⁵, while R⁵ is as hereinbefore defined,

[0079] a piperidin-3-yl group which is substituted in the 1 position bythe group R⁵, while R⁵ is as hereinbefore defined,

[0080] a piperidin-4-yl group which is substituted in the 1 position bythe group R⁵, while R⁵ is as hereinbefore defined, or

[0081] a tetrahydrofuran-3-yl, tetrahydropyran-3-yl ortetrahydropyran-4-yl group,

[0082] R^(d) denotes a hydrogen atom,

[0083] a C₁₋₃-alkyloxy group,

[0084] a methoxy group which is substituted by one to three fluorineatoms,

[0085] an ethyloxy group which is substituted in the 2 position by agroup R⁶ or R⁷, while R⁶ is as hereinbefore defined and

[0086] R⁷ denotes a hydroxy, C₁₋₃-alkyloxy, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)amino, bis-(2-methoxyethyl)-amino, pyrrolidin-1-yl,piperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl,2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl,8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, piperazin-1-yl or a4-C₁₋₃-alkyl-piperazin-1-yl group, or

[0087] a formylamino, C₁₋₄-alkylcarbonylamino,C₁₋₃-alkyloxy-C₁₋₃-alkyl-carbonylamino, C₁₋₄-alkyloxycarbonylamino,aminocarbonylamino, C₁₋₃-alkylaminocarbonylamino,di-(C₁₋₃-alkyl)aminocarbonylamino, pyrrolidin-1-ylcarbonylamino,piperidin-1-ylcarbonylamino, piperazin-1-ylcarbonylamino,4-C₁₋₃-alkyl-piperazin-1-ylcarbonylamino-morpholin-4-ylcarbonylamino ora C₁₋₄-alkylsulphonylamino group,

[0088] a propyloxy group which is substituted in the 3 position by agroup R⁶ or R⁷, while R⁶ and R⁷ are as hereinbefore defined, or

[0089] a butyloxy group which is substituted in the 4 position by agroup R⁶ or R⁷, while R⁶ and R⁷ are as hereinbefore defined, and

[0090] X denotes a nitrogen atom,

[0091] while, unless stated otherwise, the abovementioned alkyl groupsmay be straight-chained or branched,

[0092] their tautomers, their stereoisomers, their mixtures and theirsalts.

[0093] Particularly preferred compounds of the above general formula Iare those wherein

[0094] R^(a) denotes a hydrogen atom,

[0095] R^(b) denotes a 3-ethynylphenyl, 3-bromophenyl,3,4-difluorophenyl or 3-chloro-4-fluoro-phenyl group,

[0096] a 3-chloro-4-benzyloxy-phenyl,3-chloro-4-[(3-fluoro-benzyl)oxy]-phenyl, 4-(pyridin-3-yloxy)-phenyl,4-[(6-methyl-pyridin-3-yl)oxy]-phenyl,3-methyl-4-(pyridin-3-yloxy)-phenyl,3-methyl-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl,3-chloro-4-(pyridin-3-yloxy)-phenyl or3-chloro-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl group,

[0097] R^(c) denotes a cyclohexyl group which is substituted in the 3position or in the 4 position by a group R⁴—N—R⁵, while

[0098] R⁴ denotes a hydrogen atom, a methyl or ethyl group and

[0099] R⁵ denotes a hydrogen atom, a methyl, aminocarbonylmethyl,methylamino-carbonylmethyl, dimethylaminocarbonylmethyl,pyrrolidin-1-ylcarbonylmethyl, piperidin-1-ylcarbonylmethyl,piperazin-1-ylcarbonylmethyl, 4-methylpiperazin-1-ylcarbonylmethyl,morpholin-4-ylcarbonylmethyl, 2-(morpholin-4-yl-carbonyl)ethyl or3-(morpholin-4-yl-carbonyl)propyl group,

[0100] an ethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl,2-methoxyethyl, 3-methoxypropyl, 2-(butyloxycarbonylamino)-ethyl,2-aminoethyl, 3-aminopropyl, 2-(acetylamino)ethyl,3-(acetylamino)propyl, 2-(ethylcarbonylamino)ethyl,3-(ethylcarbonylamino)propyl, 2-(propylcarbonylamino)ethyl,3-(propylcarbonylamino)propyl, 2-(ethylaminocarbonylamino)ethyl,3-(ethylaminocarbonylamino)propyl, 2-(dimethylaminocarbonylamino)ethyl,3-(dimethylaminocarbonylamino)propyl,2-(morpholin-4-ylcarbonylamino)ethyl,3-(morpholin-4-ylcarbonylamino)propyl, 2-(methylsulphonyl)ethyl,3-(methylsulphonyl)propyl, 2-(methylsulphonyl-amino)ethyl or a3-(methylsulphonylamino)propyl group,

[0101] a 2-(2-oxo-pyrrolidin-1-yl)ethyl, 2-(2-oxopiperidin-1-yl)ethyl,2-(3-oxo-morpholin-4-yl)ethyl, 2-(2-oxo-imidazolidin-1-yl)ethyl,2-(2-oxo-3-methyl-imidazolidin-1-yl)ethyl,2-(2-oxo-hexahydropyrimidin-1-yl)ethyl or a2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)ethyl group,

[0102] a 3-(2-oxo-pyrrolidin-1-yl)propyl, 3-(2-oxopiperidin-1-yl)propyl,3-(3-oxo-morpholin-4-yl)propyl, 3-(2-oxo-imidazolidin-1-yl)propyl,3-(2-oxo-3-methyl-imidazolidin-1-yl)propyl,3-(2-oxo-hexahydropyrimidin-1-yl)propyl or a3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)propyl group,

[0103] a methylsulphonyl, ethylsulphonyl, 3-chloropropylsulphonyl,2-(morpholin-4-yl)-ethylsulphonyl or a3-(morpholin-4-yl)-propylsulphonyl group,

[0104] a propyloxycarbonyl or butyloxycarbonyl group,

[0105] a formyl, acetyl, ethylcarbonyl, propylcarbonyl, methoxyacetyl,(2-methoxyethyl)carbonyl, (3-methoxypropyl)carbonyl,tetrahydrofuran-2-ylcarbonyl, tetrahydropyran-4-ylcarbonyl, aminoacetyl,methylaminoacetyl, dimethylaminoacetyl, morpholin-4-ylacetyl,[2-(morpholin-4-yl)ethyl]carbonyl, [3-(morpholin-4-yl)propyl]carbonyl ora methylsulphonylacetyl group,

[0106] a cyano, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl,propylaminocarbonyl, (2-methoxyethyl)aminocarbonyl,N-methyl-N-(2-methoxyethyl)-aminocarbonyl,(3-methoxypropyl)aminocarbonyl,N-methyl-N-(3-methoxypropyl)-aminocarbonyl, phenylaminocarbonyl,pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,2-methylmorpholin-4-ylcarbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl,homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-[2.2.1]hept-5-ylcarbonyl,3-oxa-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl,8-oxa-3-aza-bicyclo[3.2.1]oct-3-ylcarbonyl,4-methylpiperazin-1-ylcarbonyl, aminosulphonyl, methylaminosulphonyl,dimethylaminosulphonyl or a morpholin-4-ylsulphonyl group,

[0107] a cyclohexyl group which is substituted in the 3 position or inthe 4 position by a group R⁶, while

[0108] R⁶ denotes a 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl,3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl,2-oxo-3-methyl-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl or a2-oxo-3-methyl-hexahydropyrimidin-1-yl group,

[0109] a pyrrolidin-3-yl group which is substituted in the 1 position bythe group R⁵, while R⁵ is as hereinbefore defined,

[0110] a piperidin-3-yl group which is substituted in the 1 position bythe group R⁵, while R⁵ is as hereinbefore defined,

[0111] a piperidin-4-yl group which is substituted in the 1 position bythe group R⁵, while R⁵ is as hereinbefore defined,

[0112] a tetrahydrofuran-3-yl, tetrahydropyran-3-yl ortetrahydropyran-4-yl group,

[0113] R^(d) denotes a hydrogen atom,

[0114] a methoxy, difluoromethoxy or ethyloxy group,

[0115] an ethyloxy group which is substituted in the 2 position by agroup R⁶ or R⁷, while R⁶ is as hereinbefore defined and

[0116] R⁷ denotes a hydroxy, methoxy, ethoxy, amino, dimethylamino,diethylamino, bis-(2-methoxyethyl)-amino, pyrrolidin-1-yl,piperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl,2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl,8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, piperazin-1-yl,4-methylpiperazin-1-yl or 4-ethylpiperazin-1-yl group, or

[0117] an acetylamino, ethylcarbonylamino, propylcarbonylamino,butylcarbonylamino, methoxyacetylamino, butyloxycarbonylamino,ethylaminocarbonylamino, dimethylaminocarbonylamino,pyrrolidin-1-ylcarbonylamino, piperidin-1-ylcarbonylamino,morpholin-4-ylcarbonylamino, methylsulphonylamino, ethylsulphonylaminoor butylsulphonylamino group,

[0118] a propyloxy group which is substituted in the 3 position by agroup R⁶ or R⁷, while R⁶ and R⁷ are as hereinbefore defined, or

[0119] a butyloxy group which is substituted in the 4 position by agroup R⁶ or R⁷, while R⁶ and R⁷ are as hereinbefore defined, and

[0120] X denotes a nitrogen atom,

[0121] while, unless stated otherwise, the abovementioned alkyl groupsmay be straight-chained or branched,

[0122] their tautomers, their stereoisomers, their mixtures and theirsalts.

[0123] Most particularly preferred compounds of general formula I arethose wherein

[0124] R^(a) denotes a hydrogen atom,

[0125] R^(b) denotes a 3-bromophenyl, 3,4-difluorophenyl,3-chloro-4-fluoro-phenyl or a 3-ethynylphenyl group, or

[0126] a 3-chloro-4-benzyloxy-phenyl,3-chloro-4-[(3-fluorbenzyl)oxy]-phenyl, 4-(pyridin-3-yloxy)-phenyl,4-[(6-methyl-pyridin-3-yl)oxy]-phenyl,3-methyl-4-(pyridin-3-yloxy)-phenyl,3-methyl-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl,3-chloro-4-(pyridin-3-yloxy)-phenyl or3-chloro-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl group,

[0127] R^(c) denotes a cyclohexyl group which is substituted in the 3position by an amino, acetylamino, tert.-butyloxycarbonylamino ormethylsulphonylamino group,

[0128] a cyclohexyl group which is substituted in the 4 position by anamino, methylamino, ethylamino, dimethylamino, aminocarbonylmethylamino,methylaminocarbonylmethylamino, dimethylaminocarbonylmethylamino,morpholin-4-ylcarbonylmethylamino,[3-(morpholin-4-ylcarbonyl)propyl]amino,[2-(methylsulphonyl)ethyl]amino, [3-(methylsulphonyl)propyl]amino or[2-(methylsulphonylamino)ethyl]amino group,

[0129] a cyclohexyl group which is substituted in the 4 position by a[2-(2-oxo-pyrrolidin-1-yl)ethyl]amino,[2-(2-oxopiperidin-1-yl)ethyl]amino,[2-(2-oxo-imidazolidin-1-yl)ethyl]amino,[2-(2-oxo-3-methyl-imidazolidin-1-yl)ethyl]amino,[2-(2-oxo-hexahydropyrimidin-1-yl)ethyl]amino or[2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)ethyl]amino group,

[0130] a cyclohexyl group which is substituted in the 4 position by a[3-(2-oxo-pyrrolidin-1-yl)propyl]amino,[3-(2-oxopiperidin-1-yl)propyl]amino,[3-(2-oxo-imidazolidin-1-yl)propyl]amino,[3-(2-oxo-3-methyl-imidazolidin-1-yl)propyl]amino,[3-(2-oxo-hexahydropyrimidin-1-yl)propyl]amino or[3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)propyl]amino group,

[0131] a cyclohexyl group which is substituted in the 4 position by anacetylamino, N-(acetyl)-methylamino, aminomethylcarbonylamino,methylaminomethylcarbonylamino, dimethylaminomethylcarbonylamino,morpholin-4-ylmethylcarbonylamino, methoxyacetylamino,N-(methoxyacetyl)-methylamino, tetrahydropyran-4-ylcarbonylamino,N-(tetrahydropyran-4-ylcarbonyl)-methylamino,tert.-butyloxycarbonylamino, N-(tert.-butyloxycarbonyl)-methylamino,aminocarbonylamino, methylaminocarbonylamino,N-(ethylaminocarbonyl)-methylamino, dimethylaminocarbonylamino,N-(dimethylaminocarbonyl)-methylamino,N-(piperidin-1-ylcarbonyl)-methylamino, morpholin-4-ylcarbonylamino,N-(morpholin-4-ylcarbonyl)-methylamino orN-(4-methylpiperazin-1-ylcarbonyl)-methylamino group,

[0132] a cyclohexyl group which is substituted in the 4 position by a2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxo-morpholin-4-yl,2-oxo-imidazolidin-1-yl, 2-oxo-3-methyl-imidazolidin-1-yl,2-oxo-hexahydropyrimidin-1-yl or a2-oxo-3-methyl-hexahydropyrimidin-1-yl group,

[0133] a cyclohexyl group which is substituted in the 4 position by amethylsulphonylamino, N-(methylsulphonyl)-methylamino,ethylsulphonylamino, N-(ethylsulphonyl)-methylamino,dimethylaminosulphonylamino, N-(dimethylaminosulphonyl)-methylamino,morpholin-4-ylsulphonylamino,N-(morpholin-4-ylsulphonyl)-methylamino-3-chloropropylsulphonylamino,[2-(morpholin-4-yl)-ethyl]sulphonylamino or[3-(morpholin-4-yl)-propyl]sulphonylamino-group,

[0134] a pyrrolidin-3-yl group,

[0135] a pyrrolidin-3-yl group which is substituted in the 1 position bya methyl, acetyl, methoxyacetyl, tert.-butyloxycarbonyl,morpholin-4-ylcarbonyl or methylsulphonyl group,

[0136] a piperidin-3-yl group,

[0137] a piperidin-3-yl group which is substituted in the 1 position bya methyl, acetyl, methoxyacetyl, tert.-butyloxycarbonyl,morpholin-4-ylcarbonyl or methylsulphonyl group,

[0138] a piperidin-4-yl group which is substituted in the 1 position bya methyl, ethyl, propyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl,3-methoxypropyl, 2-(methylsulphonyl)-ethyl, 3-(methylsulphonyl)-propyl,2-(tert.-butyloxycarbonylamino)-ethyl, 2-aminoethyl,2-(acetylamino)-ethyl, 2-(ethylcarbonylamino)-ethyl,2-(propylcarbonylamino)-ethyl, 2-(ethylaminocarbonylamino)-ethyl,2-(dimethylaminocarbonylamino)-ethyl,2-(morpholin-4-ylcarbonylamino)-ethyl, 3-(acetylamino)-propyl,3-(ethylcarbonylamino)-propyl, 3-(propylcarbonylamino)-propyl,3-(ethylaminocarbonylamino)-propyl,3-(dimethylaminocarbonylamino)-propyl,3-(morpholin-4-ylcarbonylamino)-propyl, 2-(methylsulphonylamino)-ethyl,3-(methylsulphonylamino)-propyl, (aminocarbonyl)methyl,(methylaminocarbonyl)methyl, (dimethylaminocarbonyl)methyl,(pyrrolidin-1-ylcarbonyl)methyl, (morpholin-4-ylcarbonyl)methyl,2-(morpholin-4-ylcarbonyl)-ethyl or 3-(morpholin-4-ylcarbonyl)-propylgroup, a piperidin-4-yl group which is substituted in the 1 position bya 2-(2-oxo-pyrrolidin--1-yl)-ethyl, 2-(2-oxopiperidin-1-yl)-ethyl,2-(3-oxomorpholin-4-yl)-ethyl, 2-(2-oxo-imidazolidin-1-yl)-ethyl,2-(2-oxo-3-methyl-imidazolidin-1-yl)-ethyl,2-(2-oxo-hexahydropyrimidin-1-yl)-ethyl or2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-ethyl group,

[0139] a piperidin-4-yl group which is substituted in the 1 position bya 3-(2-oxo-pyrrolidin-1-yl)-propyl, 3-(2-oxopiperidin-1-yl)-propyl,3-(3-oxomorpholin-4-yl)-propyl, 3-(2-oxo-imidazolidin-1-yl)-propyl,3-(2-oxo-3-methyl-imidazolidin-1-yl)-propyl,3-(2-oxo-hexahydropyrimidin-1-yl)-propyl or3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-propyl group,

[0140] a piperidin-4-yl group which is substituted in the 1 position bya formyl, acetyl, methoxyacetyl, (2-methoxyethyl)carbonyl,(3-methoxypropyl)carbonyl, methylsulphonylacetyl, aminoacetyl,methylaminoacetyl, (dimethylamino)acetyl, (morpholin-4-yl)acetyl,[2-(morpholin-4-yl)-ethyl]carbonyl, [3-(morpholin-4-yl)-propyl]carbonyl,tetrahydrofuran-2-ylcarbonyl or tetrahydropyran-4-ylcarbonyl group,

[0141] a piperidin-4-yl group which is substituted in the 1 position bya cyano, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl,(2-methoxyethyl)aminocarbonyl,N-methyl-N-(2-methoxyethyl)-aminocarbonyl,(3-methoxypropyl)aminocarbonyl,N-methyl-N-(3-methoxypropyl)-aminocarbonyl, isopropylaminocarbonyl,phenylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl,pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,2-methylmorpholin-4-ylcarbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl,homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl,3-oxa-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl,8-oxa-3-aza-bicyclo[3.2.1]oct-3-ylcarbonyl,4-methylpiperazin-1-ylcarbonyl, isopropyloxycarbonyl ortert.-butyloxycarbonyl group,

[0142] a piperidin-4-yl group which is substituted in the 1 position bya methylsulphonyl, ethylsulphonyl, [2-(morpholin-4-yl)-ethyl]sulphonyl,[3-(morpholin-4-yl)-propyl]sulphonyl, aminosulphonyl,methylaminosulphonyl, dimethylaminosulphonyl or morpholin-4-ylsulphonylgroup, or

[0143] a tetrahydrofuran-3-yl, tetrahydropyran-3-yl ortetrahydropyran-4-yl group,

[0144] R^(d) denotes a hydrogen atom,

[0145] a methoxy, difluoromethoxy or ethyloxy group,

[0146] a 2-(morpholin-4-yl)ethyloxy, 3-(morpholin-4-yl)propyloxy or4-(morpholin-4-yl)butyloxy group,

[0147] a 3-(dimethylamino)propyloxy, 3-(diethylamino)propyloxy,3-[bis-(2-methoxyethyl)-amino]propyloxy, 3-(piperazin-1-yl)propyloxy,3-(4-methylpiperazin-1-yl)propyloxy or3-(4-ethylpiperazin-1-yl)propyloxy group,

[0148] a 3-(homomorpholin-4-yl)-propyloxy,3-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-propyloxy,3-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-propyloxy or3-(8-oxa-3-aza-[3.2.1]oct-3-yl)-propyloxy group,

[0149] a 2-(2-oxo-pyrrolidin-1-yl)-ethyloxy,2-(2-oxopiperidin-1-yl)-ethyloxy, 2-(3-oxomorpholin-4-yl)-ethyloxy,2-(2-oxo-imidazolidin-1-yl)-ethyloxy,2-(2-oxo-3-methyl-imidazolidin-1-yl)-ethyloxy,2-(2-oxo-hexahydropyrimidin-1-yl)-ethyloxy or2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-ethyloxy group,

[0150] a 3-(2-oxo-pyrrolidin-1-yl)-propyloxy,3-(2-oxopiperidin-1-yl)-propyloxy, 3-(3-oxomorpholin-4-yl)-propyloxy,3-(2-oxo-imidazolidin-1-yl)-propyloxy,3-(2-oxo-3-methyl-imidazolidin-1-yl)-propyloxy,3-(2-oxo-hexahydropyrimidin-1-yl)-propyloxy or3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-propyloxy group,

[0151] a 2-(methoxy)-ethyloxy, 2-(tert.-butyloxycarbonylamino)-ethyloxy,2-(amino)-ethyloxy, 2-(acetylamino)-ethyloxy,2-(ethylcarbonylamino)-ethyloxy, 2-(propylcarbonylamino)-ethyloxy,2-(isobutylcarbonylamino)-ethyloxy, 2-(methoxyacetylamino)-ethyloxy,2-(ethylaminocarbonylamino)-ethyloxy,2-(dimethylaminocarbonylamino)-ethyloxy,2-(pyrrolidin-1-ylcarbonylamino)-ethyloxy,2-(piperidin-1-ylcarbonylamino)-ethyloxy,2-(morpholin-4-ylcarbonylamino)-ethyloxy,2-(methylsulphonylamino)-ethyloxy group,2-(ethylsulphonylamino)-ethyloxy or 2-(butylsulphonylamino)-ethyloxygroup, or a 3-(tert.-butyloxycarbonylamino)-propyloxy,3-(amino)-propyloxy, 3-(acetylamino)-propyloxy or3-(methylsulphonylamino)-propyloxy group, and

[0152] X denotes a nitrogen atom, their tautomers, their stereoisomers,their mixtures and their salts.

[0153] Particularly preferred compounds of general formula I are thosewherein

[0154] R^(a) denotes a hydrogen atom,

[0155] R^(b) preferably denotes a 3-chloro-4-fluoro-phenyl group or alsoa 3-ethynylphenyl group,

[0156] R^(c) denotes a cyclohexyl group which is substituted in the 3position by an amino, acetylamino, tert.-butyloxycarbonylamino ormethylsulphonylamino group,

[0157] a cyclohexyl group which is substituted in the 4 position by anamino, methylamino, dimethylamino, acetylamino, N-(acetyl)-methylamino,methoxyacetylamino, N-(methoxyacetyl)-methylamino,tetrahydropyran-4-ylcarbonylamino,N-(tetrahydropyran-4-ylcarbonyl)-methylamino,tert.-butyloxycarbonylamino, N-(tert.-butyloxycarbonyl)-methylamino,N-(ethylaminocarbonyl)-methylamino, dimethylaminocarbonylamino,N-(dimethylaminocarbonyl)-methylamino,N-(piperidin-1-ylcarbonyl)-methylamino, morpholin-4-ylcarbonylamino,N-(morpholin-4-ylcarbonyl)-methylamino,N-(4-methylpiperazin-1-ylcarbonyl)-methylamino, methylsulphonylamino,N-(methylsulphonyl)-methylamino, ethylsulphonylamino,N-(ethylsulphonyl)-methylamino, dimethylaminosulphonylamino,N-(dimethylaminosulphonyl)-methylamino, morpholin-4-ylsulphonylamino,N-(morpholin-4-ylsulphonyl)-methylamino, 3-chloropropylsulphonylamino,or [3-(morpholin-4-yl)-propyl]sulphonylamino group,

[0158] a pyrrolidin-3-yl group,

[0159] a pyrrolidin-3-yl group which is substituted in the 1 position bya tert.-butyloxycarbonyl or methylsulphonyl group,

[0160] a piperidin-3-yl group,

[0161] a piperidin-3-yl group which is substituted in the 1 position bya tert.-butyloxycarbonyl or methylsulphonyl group,

[0162] a piperidin-4-yl group,

[0163] a piperidin-4-yl group which is substituted in the 1 position bya methyl, (aminocarbonyl)methyl, (dimethylaminocarbonyl)methyl,(morpholin-4-ylcarbonyl)methyl, 2-(tert.-butyloxycarbonylamino)ethyl,2-aminoethyl, 2-(acetylamino)ethyl, 2-(methylsulphonylamino)ethyl,cyano, acetyl, methoxyacetyl, (dimethylamino)acetyl,(morpholin-4-yl)acetyl, tetrahydropyran-4-ylcarbonyl,ethylaminocarbonyl, isopropylaminocarbonyl, phenylaminocarbonyl,dimethylaminocarbonyl, diethylaminocarbonyl, pyrrolidin-1-ylcarbonyl,piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,2-methylmorpholin-4-ylcarbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl,homomorpholin-4-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl,isopropyloxycarbonyl, tert.-butyloxycarbonyl, methylsulphonyl,dimethylaminosulphonyl or morpholin-4-ylsulphonyl group, or

[0164] a tetrahydrofuran-3-yl, tetrahydropyran-3-yl ortetrahydropyran-4-yl group,

[0165] R^(d) denotes a hydrogen atom,

[0166] a methoxy or ethyloxy group,

[0167] a 2-(morpholin-4-yl)ethyloxy, 3-(morpholin-4-yl)propyloxy or4-(morpholin-4-yl)butyloxy group,

[0168] a 2-(3-methyl-2-oxo-hexahydropyrimidin-1-yl)-ethyloxy group,

[0169] a 2-(methoxy)-ethyloxy, 2-(tert.-butyloxycarbonylamino)-ethyloxy,2-amino-ethyloxy, 2-(acetylamino)-ethyloxy or2-(methylsulphonylamino)-ethyloxy group or

[0170] a 3-(tert.-butyloxycarbonylamino)-propyloxy, 3-amino-propyloxy,3-(acetylamino)-propyloxy or 3-(methylsulphonylamino)-propyloxy group,and

[0171] X denotes a nitrogen atom,

[0172] their tautomers, their stereoisomers, their mixtures and theirsalts.

[0173] Of the bicyclic heterocyclic groups of general formula I asdescribed above as well as the sub-groups specified as being preferred,particularly preferred, most particularly preferred and especiallypreferred, special mention should be made of those compounds wherein

[0174] (a) R^(c) denotes a cyclohexyl group substituted in the 4position,

[0175] (b) R^(c) denotes a pyrrolidin-3-yl group optionally substitutedin the I position,

[0176] (c) R^(c) denotes a piperidin-3-yl group optionally substitutedin the 1 position,

[0177] (d) R^(c) denotes a piperidin-4-yl group optionally substitutedin the 1 position,

[0178] (e) R^(c) denotes a tetrahydrofuran-3-yl group,

[0179] (f) R^(c) denotes a tetrahydropyran-3-yl group, or

[0180] (g) R^(c) denotes a tetrahydropyran-4-yl group,

[0181] while R^(a), R^(b), R^(d) and X in each case are as hereinbeforedefined.

[0182] The following are mentioned as examples of particularly preferredcompounds of general formula I:

[0183] (1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-methoxy-quinazoline,

[0184] (2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-methoxy-quinazoline,

[0185] (3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((R)-tetrahydrofuran-3-yloxy)-7-methoxy-quinazoline,

[0186] (4)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexane-1-yloxy)-7-methoxy-quinazoline,

[0187] (5)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexane-1-yloxy)-7-methoxy-quinazoline,

[0188] (6)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline,

[0189] (7)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,

[0190] (8)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{[3-(morpholin-4-yl)-propyl]sulphonylamino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,

[0191] (9)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,

[0192] (10)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{[3-(morpholin-4-yl)-propyl]sulphonylamino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,

[0193] (11)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,

[0194] (12)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,

[0195] (13)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,

[0196] (14)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,

[0197] (15)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)sulphonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,

[0198] (16)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,

[0199] (17)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,

[0200] (18)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,

[0201] (19)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,

[0202] (20)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline,

[0203] (21)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazolineand (22)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,

[0204] as well as their salts.

[0205] The compounds of general formula I may be prepared for example bythe following methods:

[0206] a) reacting a compound of general formula

[0207] wherein

[0208] R^(a), R^(b), R^(d) and X are as hereinbefore defined, with acompound of general formula

Z¹-R^(c),  (III)

[0209] wherein

[0210] R^(c) is as hereinbefore defined and Z¹ denotes a leaving groupsuch as a halogen atom, e.g. a chlorine or bromine atom, a sulphonyloxygroup such as a methanesulphonyloxy or p-toluenesulphonyloxy group or ahydroxy group.

[0211] With a compound of general formula III wherein Z¹ denotes ahydroxy group, the reaction is carried out in the presence of adehydrating agent, preferably in the presence of of a phosphine and anazodicarboxylic acid derivative such as e.g. triphenylphosphine/diethylazodicarboxylate, conveniently in a solvent such as methylene chloride,acetonitrile, tetrahydrofuran, dioxane, toluene orethylenglycoldiethylether at temperatures between −50 and 150° C., butpreferably at temperatures between −20 and 80° C.

[0212] b) In order to prepare compounds of general formula I whereinR^(d) denotes one of the optionally substituted alkyloxy groupsmentioned hereinbefore:

[0213] reacting a compound of general formula

[0214] wherein R^(a), R^(b), R^(c) and X are as hereinbefore defined,with a compound of general formula

Z²-R^(d′),  (V)

[0215]  wherein R^(d′) denotes a C₁₋₄-alkyl group, a methyl groupsubstituted by 1 to 3 fluorine atoms, an ethyl group substituted by 1 to5 fluorine atoms, a C₂₋₄-alkyl group substituted by a group R⁶ or R⁷,where R⁶ and R⁷ are as hereinbefore defined, a C₁₋₄-alkyl group which issubstituted by a pyrrolidinyl, piperidinyl or homopiperidinyl groupsubstituted in the 1 position by the group R⁸, or a C₁₋₄-alkyl groupwhich is substituted by a morpholinyl group substituted in the 4position by the group R⁸, while R⁸ in each case is as hereinbeforedefined, and

[0216] Z² denotes a leaving group such as a halogen atom, analkylsulphonyloxy, arylsulphonyloxy or a hydroxy group.

[0217] If the leaving group is a halogen atom such as a chlorine,bromine or iodine atom or an alkylsulphonyloxy or arylsulphonyloxy groupsuch as the methanesulphonyloxy or p-toluenesulphonyloxy group, thereaction is preferably carried out in the presence of an organic orinorganic base such as potassium carbonate, sodium hydride orN-ethyl-diisopropylamine. If the leaving group is a hydroxy group, thereaction is carried out in the presence of a dehydrating agent,preferably in the presence of a phosphine and an azodicarboxylic acidderivative such as e.g. triphenylphosphine/diethyl azodicarboxylate.

[0218] c) In order to prepare compounds of general formula I whereinR^(d) denotes one of the abovementioned alkyloxy groups which issubstituted by an optionally substituted amino, alkylamino ordialkylamino group or by an optionally substituted heterocyclic groupbound via an iminonitrogen atom:

[0219] reacting a compound of general formula

[0220]  wherein R^(a), R^(b), R^(c) and X are as hereinbefore definedand Z³ denotes a leaving group such as a halogen atom, e.g. a chlorineor bromine atom or a sulphonyloxy group such as a methanesulphonyloxy orp-toluenesulphonyloxy group,

[0221] with ammonia, a corresponding, optionally substituted alkylamine,dialkylamine or an imino compound or the suitable salts or derivativesthereof, such as morpholine, for example.

[0222] d) In order to prepare compounds of general formula I whereinR^(d) denotes a hydroxy group:

[0223] Cleaving a protecting group from a compound of general formula

[0224]  wherein R^(a), R^(b), R^(c) and X are as hereinbefore definedand R^(d″) denotes a group which may be converted into a hydroxy group,for example an optionally substituted benzyloxy group, atrimethylsilyloxy, acetyloxy, benzoyloxy, methoxy, ethoxy, tert-butoxyor trityloxy group.

[0225] The protecting group is cleaved for example by hydrolysis in anaqueous solvent, e.g. in water, isopropanol/water, acetic acid/water,tetrahydrofuran/water or dioxan/water, in the presence of an acid suchas trifluoroacetic acid, hydrochloric acid or sulphuric acid or in thepresence of an alkali metal base such as sodium hydroxide or potassiumhydroxide or aprotically, e.g. in the presence of iodotrimethylsilane,at temperatures between 0 and 120° C., preferably at temperaturesbetween 10 and 100° C.

[0226] However, a benzyl or methoxybenzyl group is cleaved, for example,hydrogenolytically, e.g. with hydrogen in the presence of a catalystsuch as palladium/charcoal in a suitable solvent such as methanol,ethanol, ethyl acetate or glacial acetic acid, optionally with theaddition of an acid such as hydrochloric acid at temperatures between 0and 100° C., but preferably at ambient temperatures between 20 and 60°C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.A 2,4-dimethoxybenzyl group, however, is preferably cleaved intri-fluoroacetic acid in the presence of anisole.

[0227] A tert.butyl or benzyl group is cleaved for example by treatingwith an acid such as trifluoroacetic acid, hydrochloric acid orhydrobromic acid or by treating with iodotrimethylsilane, optionallyusing a solvent such as methylene chloride, dioxan, methanol or diethylether.

[0228] e) In order to prepare compounds of general formula I whereinR^(c) contains a —NH— group:

[0229] cleaving a protecting group from a compound of general formula

[0230]  wherein R^(a), R^(b), R^(d) and X are as hereinbefore definedand R^(c) has the meanings given for R^(c) hereinbefore, with theproviso that R^(c) contains a protected nitrogen atom.

[0231] Conventional protecting groups for an amino, alkylamino or iminogroup are for example the formyl, acetyl, trifluoroacetyl,ethoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, benzyl,methoxybenzyl or 2,4-dimethoxybenzyl group, while for the amino groupthe phthalyl group is an additional possibility.

[0232] The protecting group is cleaved for example by hydrolysis in anaqueous solvent, e.g. in water, isopropanol/water, acetic acid/water,tetrahydrofuran/water or dioxan/water, in the presence of an acid suchas trifluoroacetic acid, hydrochloric acid or sulphuric acid or in thepresence of an alkali metal base such as sodium hydroxide or potassiumhydroxide or aprotically, e.g. in the presence of iodotrimethylsilane,at temperatures between 0 and 120° C., preferably at temperaturesbetween 10 and 100° C.

[0233] However, a benzyl, methoxybenzyl or benzyloxycarbonyl group iscleaved, for example hydrogenolytically, e.g. with hydrogen in thepresence of a catalyst such as palladium/charcoal in a suitable solventsuch as methanol, ethanol, ethyl acetate or glacial acetic acid,optionally with the addition of an acid such as hydrochloric acid attemperatures between 0 and 100° C., but preferably at ambienttemperatures between 20 and 60° C., and at a hydrogen pressure of 1 to 7bar, but preferably 3 to 5 bar. A 2,4-dimethoxybenzyl group, however, ispreferably cleaved in trifluoroacetic acid in the presence of anisole.

[0234] A tert.butyl or tert.butyloxycarbonyl group is preferably cleavedby treating with an acid such as trifluoroacetic acid or hydrochloricacid or by treating with iodotrimethylsilane optionally using a solventsuch as methylene chloride, dioxan, methanol or diethyl ether.

[0235] A trifluoroacetyl group is preferably cleaved by treating with anacid such as hydrochloric acid, optionally in the presence of a solventsuch as acetic acid at temperatures between 50 and 120° C. or bytreating with sodium hydroxide solution, optionally in the presence of asolvent such as tetrahydrofuran at temperatures between 0 and 50° C.

[0236] A phthalyl group is preferably cleaved in the presence ofhydrazine or a primary amine such as methylamine, ethylamine orn-butylamine in a solvent such as methanol, ethanol, isopropanol,toluene/water or dioxane at temperatures between 20 and 50° C.

[0237] f) In order to prepare compounds of general formula I whereinR^(c) contains an alkyl group substituted by an optionally substitutedamino, alkylamino or dialkyamino group or by an optionally substitutedheterocyclic group bound via a nitrogen atom:

[0238] reacting a compound of general formula

[0239]  wherein R^(a), R^(b), R^(d) and X are as hereinbefore defined,Z³ denotes a leaving group, for example a halogen atom such as achlorine or bromine atom, or a sulphonyloxy group such as amethanesulphonyloxy or p-toluenesulphonyloxy group, and R^(c) has themeanings given for R^(c) hereinbefore with the proviso that a hydrogenatom bound to an aliphatic carbon atom is replaced by the group Z³,

[0240] with ammonia, a corresponding, optionally substituted alkylamine,dialkylamine or

[0241] an imino compound or the appropriate salts or derivativesthereof, such as morpholine, for example.

[0242] If according to the invention a compound of general formula I isobtained which contains an amino, alkylamino or imino group, this may beconverted by acylation, cyanation or sulphonylation into a correspondingacyl, cyano or sulphonyl compound of general formula I, the acylatingagents being for example isocyanate, carbamoyl chloride, carboxylic acidhalide, carboxylic acid anhydride and carboxylic acids with activatingagents such as N,N′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimideor O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium-tetrafluoroborate,the sulphonylating agents being sulphonyl halides and the cyanatingagents being chlorine or bromocyanogen, and/or

[0243] if a compound of general formula I is obtained which contains anamino, alkylamino or imino group, this may be converted by alkylation orreductive alkylation into a corresponding alkyl compound of generalformula I and/or

[0244] if a compound of general formula I is obtained which contains achloro-C₁₋₄-alkylsulphonyl or bromo-C₁₋₄-alkylsulphonyl group, this maybe converted by reaction with an amine into a correspondingamino-C₁₋₄-alkylsulphonyl compound and/or

[0245] if a compound of general formula I is obtained which contains atert.-butyloxycarbonylamino, N-alkyl-N-(tert.-butyloxycarbonyl)amino ora N-tert.-butyloxycarbonylimino group, this may be converted into acorresponding amino, alkylamino or imino compound of general formula Iby treatment with an acid such as hydrochloric acid or trifluoroaceticacid.

[0246] In the reactions described hereinbefore, any reactive groupspresent such as hydroxy, carboxy or imino groups may be protected duringthe reaction by conventional protecting groups which are cleaved againafter the reaction.

[0247] For example, a protecting group for a hydroxy group may be atrimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group.

[0248] Protecting groups for an amino, alkylamino or imino group may bea formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl,benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group,for example.

[0249] Any protecting group used is optionally subsequently cleaved forexample by hydrolysis in an aqueous solvent, e.g. in water,isopropanol/water, acetic acid/water, tetrahydrofuran/water ordioxan/water, in the presence of an acid such as trifluoroacetic acid,hydrochloric acid or sulphuric acid or in the presence of an alkalimetal base such as sodium hydroxide or potassium hydroxide oraprotically, e.g. in the presence of iodotrimethylsilane, attemperatures between 0 and 120° C., preferably at temperatures between10 and 100° C.

[0250] However, a benzyl, methoxybenzyl or benzyloxycarbonyl group iscleaved, for example, hydrogenolytically, e.g. with hydrogen in thepresence of a catalyst such as palladium/charcoal in a suitable solventsuch as methanol, ethanol, ethyl acetate or glacial acetic acid,optionally with the addition of an acid such as hydrochloric acid attemperatures between 0 and 100° C., but preferably at ambienttemperatures between 20 and 60° C., and at a hydrogen pressure of 1 to 7bar, but preferably 3 to 5 bar. A 2,4-dimethoxybenzyl group, however, ispreferably cleaved in trifluoroacetic acid in the presence of anisole.

[0251] A tert.butyl or tert.butyloxycarbonyl group is preferably cleavedby treating with an acid such as trifluoroacetic acid or hydrochloricacid or by treating with iodotrimethylsilane optionally using a solventsuch as methylene chloride, dioxan, methanol or diethyl ether.

[0252] A trifluoroacetyl group is preferably cleaved by treating with anacid such as hydrochloric acid, optionally in the presence of a solventsuch as acetic acid at temperatures between 50 and 120° C. or bytreating with sodium hydroxide solution, optionally in the presence of asolvent such as tetrahydrofuran at temperatures between 0 and 50° C.Moreover, the compounds of general formula I obtained may be resolvedinto their enantiomers and/or diastereomers, as mentioned hereinbefore.Thus, for example, cis/trans mixtures may be resolved into their cis andtrans isomers, and compounds with at least one optically active carbonatom may be separated into their enantiomers.

[0253] Thus, for example, the cis/trans mixtures may be resolved bychromatography into the cis and trans isomers thereof, the compounds ofgeneral formula I obtained which occur as racemates may be separated bymethods known per se (cf. Al-linger N. L. and Eliel E. L. in “Topics inStereochemistry”, Vol. 6, Wiley Interscience, 1971) into their opticalantipodes and compounds of general formula I with at least 2 asymmetriccarbon atoms may be resolved into their diastereomers on the basis oftheir physical-chemical differences using methods known per se, e.g. bychromatography and/or fractional crystallisation, and, if thesecompounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

[0254] The enantiomers are preferably separated by column separation onchiral phases or by recrystallisation from an optically active solventor by reacting with an optically active substance which forms salts orderivatives such as e.g. esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g. on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, aspartic acid or quinicacid. An optically active alcohol may be for example (+) or (−)-mentholand an optically active acyl group in amides, for example, may be a(+)-or (−)-menthyloxycarbonyl.

[0255] Furthermore, the compounds of formula I may be converted into thesalts thereof, particularly for pharmaceutical use into thephysiologically acceptable salts with inorganic or organic acids. Acidswhich may be used for this purpose include for example hydrochloricacid, hydrobromic acid, sulphuric acid, methanesulphonic acid,phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid,tartaric acid or maleic acid.

[0256] The compounds of general formulae II to I used as startingmaterials are known from the literature in some cases or may be obtainedby methods known from the literature (cf. Examples I to XXII) or themethods described hereinbefore, optionally with the additional use ofprotecting groups (e.g. compounds of formula IV or VII and VIII).

[0257] As already mentioned hereinbefore, the compounds of generalformula I according to the invention and the physiologically acceptablesalts thereof have valuable pharmacological properties, particularly aninhibiting effect on signal transduction mediated by the EpidermalGrowth Factor receptor (EGF-R), whilst this may be achieved for exampleby inhibiting ligand bonding, receptor dimerisation or tyrosine kinaseitself. It is also possible that the transmission of signals tocomponents located further down is blocked.

[0258] The biological properties of the new compounds were investigatedas follows:

[0259] The inhibition of human EGF-receptor kinase was determined usingthe cytoplasmic tyrosine kinase domain (methionine 664 to alanine 1186based on the sequence published in Nature 309 (1984), 418). For this theprotein was expressed in Sf9 insect cells as GST fusion protein usingthe Baculovirus expression system.

[0260] The enzyme activity was measured in the presence or absence ofthe test compounds in serial dilutions. The polymer pEY (4:1) obtainedfrom SIGMA was used as the substrate. Biotinylated pEY (bio-pEY) wasadded as the tracer substrate. 100 μl of reaction solution contained 10μl of the inhibitor in 50% DMSO, 20 μl of the substrate solution (200 mMHEPES pH 7.4, 50 mM magnesium acetate, 2.5 mg/ml poly(EY), 5 μg/mlbio-pEY) and 20 μl of enzyme preparation. The enzyme reaction wasstarted by the addition of 50 μl of a 100 μM ATP solution in 10 mM ofmagnesium chloride. The dilution of the enzyme preparation was adjustedso that the incorporation of phosphate in the bio-pEY was linear interms of time and quantity of enzyme. The enzyme preparation was dilutedin 20 mM HEPES pH 7.4, 1 mM EDTA, 130 mM common salt, 0.05% TritonX-100, 1 mM DTT and 10% glycerol.

[0261] The enzyme assays were carried out at ambient temperature over aperiod of 30 minutes and ended by the addition of 50 μl of a stoppingsolution (250 mM EDTA in 20 mM HEPES pH 7.4). 100 μl were placed on astreptavidine-coated microtitre plate and incubated for 60 minutes atambient temperature. Then the plate was washed with 200 μl of a washsolution (50 mM Tris, 0.05% Tween 20). After the addition of 100 μl ofan HRPO-labelled anti-PY antibody (PY20H Anti-PTyr:HRP made byTransduction Laboratories, 250 ng/ml) the preparation was incubated for60 minutes. Then the microtitre plate was washed three times with 200 μlof wash solution. The samples were then combined with 100 μl of aTMB-peroxidase solution (A:B=1:1, Kirkegaard Perry Laboratories). After10 minutes the reaction was stopped. The extinction was measured atOD_(450 nm) with an ELISA reader. All the results were measured threetimes.

[0262] The data were adapted by iterative calculation using ananalytical pogramme for sigmoidal curves (Graph Pad Prism Version 3.0)with a variable Hill pitch. All the iterative data produced had acorrelation coefficient of more than 0.9 and the upper and lower valuesof the curves showed a spread of at least a factor of 5. The activesubstance concentration which inhibits the activity of EGF receptorkinase by 50% (IC₅₀) was derived from the curves.

[0263] The following results were obtained: Compound Inhibition of EGF(Example receptor kinase Nr.) IC₅₀ [nM] 1 0.13 1 (1) 0.12 1 (2) 2 1 (3)1.1 1 (4) 0.6 1 (5) 0.6 1 (6) 0.69 1 (7) 1.6 2 4.5 2 (1) 0.16 2 (2) 0.223 0.9 3 (1) 0.14 3 (2) 0.22 3 (7) 0.7 3 (8) 0.6 3 (9) 0.2 3 (11) 0.1 3(15) 1 3 (16) 1 3 (17) 0.3 3 (18) 0.4 3 (20) 1 3 (21) 0.4 4 0.41 4 (1)0.16 7 (5) 1

[0264] The compounds of general formula I according to the inventionthus inhibit signal transduction by tyrosine kinases, as demonstrated bythe example of the human EGF receptor, and are therefore useful fortreating pathophysiological processes caused by hyperfunction oftyrosine kinases. These are e.g. benign or malignant tumours,particularly tumours of epithelial and neuroepithelial origin,metastasisation and the abnormal proliferation of vascular endothelialcells (neoangiogenesis).

[0265] The compounds according to the invention are also useful forpreventing and treating diseases of the airways and lungs which areaccompanied by increased or altered production of mucus caused bystimulation by tyrosine kinases, e.g. in inflammatory diseases of theairways such as chronic bronchitis, chronic obstructive bronchitis,asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis,cystic fibrosis, α1-antitrypsin deficiency, or coughs, pulmonaryemphysema, pulmonary fibrosis and hyperreactive airways.

[0266] The compounds are also suitable for treating diseases of thegastrointestinal tract and bile duct and gall bladder which areassociated with disrupted activity of the tyrosine kinases, such as maybe found e.g. in chronic inflammatory changes such as cholecystitis,Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinaltract or such as may occur in diseases of the gastrointestinal tractwhich are associated with increased secretions, such as Menetrier'sdisease, secreting adenomas and protein loss syndrome.

[0267] In addition, the compounds of general formula I and thephysiologically acceptable salts thereof may be used to treat otherdiseases caused by abnormal function of tyrosine kinases, such as e.g.epidermal hyperproliferation (psoriasis), benign prostate hyperplasia(BPH), inflammatory processes, diseases of the immune system,hyperproliferation of haematopoietic cells, the treatment of nasalpolyps, etc.

[0268] By reason of their biological properties the compounds accordingto the invention may be used on their own or in conjunction with otherpharmacologically active compounds, for example in tumour therapy, inmonotherapy or in conjunction with other anti-tumour therapeutic agents,for example in combination with topoisomerase inhibitors (e.g.etoposide), mitosis inhibitors (e.g. vinblastine), compounds whichinteract with nucleic acids (e.g. cis-platin, cyclophosphamide,adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors ofmetabolic processes (e.g. 5-FU etc.), cytokines (e.g. interferons),antibodies, etc. For treating respiratory tract diseases, thesecompounds may be used on their own or in conjunction with othertherapeutic agents for the airways, such as substances with asecretolytic (e.g. ambroxol, N-acetylcysteine), broncholytic (e.g.tiotropium or ipratropium or fenoterol, salmeterol, salbutamol) and/oranti-inflammatory activity (e.g. theophylline or glucocorticoids). Fortreating diseases in the region of the gastrointestinal tract, thesecompounds may also be administered on their own or in conjunction withsubstances having an effect on motility or secretion. These combinationsmay be administered either simultaneously or sequentially.

[0269] These compounds may be administered either on their own or inconjunction with other active substances by intravenous, subcutaneous,intramuscular, intraperitoneal or intranasal route, by inhalation ortransdermally or orally, whilst aerosol formulations are particularlysuitable for inhalation.

[0270] For pharmaceutical use the compounds according to the inventionare generally used for warm-blooded vertebrates, particularly humans, indoses of 0.01-100 mg/kg of body weight, preferably 0.1-15 mg/kg. Foradministration they are formulated with one or more conventional inertcarriers and/or diluents, e.g. with corn starch, lactose, glucose,microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone,citric acid, tartaric acid, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethylene glycol, propylene glycol, stearylalcohol, carboxymethylcellulose or fatty substances such as hard fat orsuitable mixtures thereof in conventional galenic preparations such asplain or coated tablets, capsules, powders, suspensions, solutions,sprays or suppositories.

[0271] The following Examples are intended to illustrate the presentinvention without restricting it:

[0272] Preparation of the Starting Compounds:

EXAMPLE I

[0273]4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-benzyloxy-quinazoline-hydrochloride

[0274] A mixture of 10.84 g4-chloro-6-(tetrahydropyran-4-yloxy)-7-benzyloxy-quinazoline and 4.50 g3-chloro-4-fluoranilin in 300 ml isopropanol is refluxed for four hoursand then left to stand overnight at ambient temperature. The precipitateformed is suction filtered, washed with isopropanol and stirred with 150ml of methanol. The suspension is stirred for another half hour atambient temperature and then suction filtered. The filter cake is washedrepeatedly with methanol and dried.

[0275] Yield: 9.07 g (60% of theory)

[0276] R_(f) value: 0.27 (silica gel, cyclohexane/ethyl acetate=1:1)

[0277] Mass spectrum (ESI⁻): m/z=478, 480 [M−H]⁻

[0278] The following compounds are obtained analogously to Example I:

[0279] (1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-benzyloxy-quinazoline-hydrochloride

[0280] R_(f) value: 0.34 (silica gel, cyclohexane/ethyl acetate=1:1)

[0281] Mass spectrum (ESI⁺): m/z=466, 468 [M+H]⁺

[0282] (2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-quinazoline-hydrochloride

[0283] R_(f) value: 0.17 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0284] Mass spectrum (ESI⁺): m/z=469, 471 [M+H]⁺

[0285] (3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-acetoxy-quinazoline-hydrochloride

[0286] R_(f) value: 0.70 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=90:10:1)

[0287] Mass spectrum (ESI⁺): m/z=527, 529 [M+H]⁺

[0288] (4) 4-[(3-ethynyl-phenyl)amino]-6-acetoxy-7-methoxy-quinazoline

[0289] R_(f) value: 0.59 (silica gel, ethyl acetate) Mass spectrum(ESI⁺): m/z=334 [M+H]⁺

[0290] (5)4-({3-chloro-4-[(3-fluorobenzyl)oxy]-phenyl}amino)-6-(acetyloxy)-7-methoxy-quinazoline

[0291] R_(f) value: 0.20 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0292] Mass spectrum (ESI⁺): m/z=466, 468 [M+H]⁺

[0293] (6)4-{[3-methyl-4-(pyridin-3-yloxy)-phenyl]amino)-6-(acetyloxy)-7-methoxy-quinazoline

[0294] The 3-methyl-4-(pyridin-3-yloxy)-aniline used (R_(f) value: 0.30(silica gel, cyclohexane/ethyl acetate=1:1)) was prepared by reactingthe sodium salt of 3-hydroxypyridine with 3-methyl-4-fluoro-nitrobenzenein dimethylformamide and subsequently hydrogenating the3-methyl-4-(pyridin-3-yloxy)-nitrobenzene (R_(f) value: 0.58 (silicagel, cyclohexane/ethyl acetate=1:1)) in the presence of palladium onactivated charcoal.

[0295] R_(f) value: 0.50 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0296] Mass spectrum (ESI⁺): m/z=415 [M−H]⁺

EXAMPLE II

[0297] 4-chloro-6-(tetrahydropyran-4-yloxy)-7-benzyloxy-quinazoline

[0298] Prepared by reacting6-(tetrahydropyran-4-yloxy)-7-benzyloxy-3H-quinazoline-4-on with thionylchloride in the presence of N,N-dimethylformamide in acetonitrile atreflux temperature.

[0299] R_(f) value: 0.90 (silica gel, ethyl acetate/methanol=9:1)

[0300] The following compounds are obtained analogously to Example II:

[0301] (1)4-chloro-6-((S)-tetrahydrofuran-3-yloxy)-7-benzyloxy-quinazoline

[0302] R_(f) value: 0.85 (silica gel, ethyl acetate/methanol=9:1)

[0303] (2) 4-chloro-6-(1-trifluoroacetyl-piperidin-4-yloxy)-quinazoline

[0304] R_(f) value: 0.92 (silica gel, ethyl acetate)

[0305] (3)4-chloro-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-acetoxy-quinazoline

[0306] EXAMPLE III

[0307] 6-(tetrahydropyran-4-yloxy)-7-benzyloxy-3H-quinazoline-4-on

[0308] A mixture of 15.08 g2-amino-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acid and 14.40 gformamidine acetate in 250 ml of absolute ethanol is refluxed overnight.The cooled reaction mixture is combined with 250 ml of water. Theprecipitate formed is suction filtered and dried at 70° C. in the dryingcupboard.

[0309] Yield: 10.00 g (65% of theory)

[0310] R_(f) value: 0.40 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0311] Mass spectrum (ESI⁺): m/z=353 [M+H]⁺

[0312] The following compounds are obtained analogously to Example III:

[0313] (1)6-((S)-tetrahydrofuran-3-yloxy)-7-benzyloxy-3H-quinazoline-4-one

[0314] R_(f) value: 0.60 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0315] Mass spectrum (ESI⁺): m/z=339 [M+H]⁺

[0316] (2)6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-3H-quinazolin-4-one

[0317] R_(f) value: 0.48 (silica gel, ethyl acetate/methanol=9:1)

[0318] Mass spectrum (ESI⁺): m/z=346 [M+H]⁺

[0319] (3)6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-hydroxy-3H-quinazolin-4-one

[0320] R_(f) value: 0.35 (silica gel, methylene chloride/methanol=9:1)

[0321] Mass spectrum (ESI⁺): m/z=362 [M+H]⁺

EXAMPLE IV

[0322] 2-amino-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic Acid

[0323] 16.40 g 2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoicacid are hydrogenated in the presence of 1.64 g Raney nickel in 800 mlof methanol at 55° C., until the calculated amount of hydrogen has beentaken up. The catalyst is filtered off and the filtrate evaporated down,whereupon the desired product crystallises out.

[0324] Yield: 15.08 g (100% of theory)

[0325] R_(f) value: 0.60 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0326] The following compounds are obtained analogously to Example IV:

[0327] (1) benzyl2-amino-4-benzyloxy-5-((S)-tetrahydrofuran-3-yloxy)-benzoate

[0328] R_(f) value: 0.70 (silica gel, cyclohexane/ethyl acetate=1:1)

[0329] Mass spectrum (ESI⁺): m/z=420 [M+H]⁺

[0330] (2)2-amino-5-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-benzoic Acid

[0331] R_(f) value: 0.43 (silica gel, methylene chloride/methanol=9:1)

[0332] Mass spectrum (ESI⁺): m/z=337 [M+H]⁺

[0333] (3)2-amino-4-hydroxy-5-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-benzoicAcid

[0334] R_(f) value: 0.23 (silica gel, methylene chloride/methanol/aceticacid=90:10:1)

EXAMPLE V

[0335] 2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic Acid

[0336] Prepared by saponification of benzyl2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoate with 1 N sodiumhydroxide solution in methanol at ambient temperature.

[0337] R_(f) value: 0.20 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0338] Mass spectrum (ESI⁺): m/z=374 [M+H]⁺

EXAMPLE VI

[0339] Benzyl 2-nitro-4-benzyloxy-5-(tetrahydro-pyran-4-yloxy)-benzoate

[0340] 42.60 g potassium-tert.-butoxide are added to 38 ml oftetrahydrofuran-4-ol in 228 ml N,N-dimethylformamide while cooling withan ice bath. The mixture is stirred for one hour at ambient temperature,then 22.90 g 6-nitro-benzo[1,3]dioxol-5-carboxylic acid are added. After1.5 hours the reaction is complete according to thin layerchromatography and 28.94 ml of benzylbromide are added dropwise whilecooling with an ice bath. The reaction mixture is stirred overnight atambient temperature, combined with 100 ml 10% citric acid and stirredfor another day at ambient temperature. Then the reaction mixture isevaporated down in vacuo at 60° C. and added to 800 ml ice water. Theaqueous phase is extracted with ethyl acetate and the combined extractsare washed with water and saturated sodium chloride solution, dried overmagnesium sulphate and evaporated.

[0341] The residue is stirred with diethyl ether, while2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acidcrystallises out as a by-product. This is filtered off and the filtrateis evaporated down. The main product remaining is benzyl2-nitro-4-benzyloxy-5-(tetrahydro-pyran-4-yloxy)-benzoate, which issaponified without any further purification to form carboxylic acid (seeExample V).

[0342] The following compounds are obtained analogously to Example VI:

[0343] (1) benzyl2-nitro-4-benzyloxy-5-((S)-tetrahydrofuran-3-yloxy)-benzoate

[0344] R_(f) value: 0.75 (silica gel, cyclohexane/ethyl acetate=1:1)

[0345] Mass spectrum (ESI⁺): m/z=450 [M+H]⁺

[0346] (2)2-nitro-4-hydroxy-5-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-benzoicAcid

[0347] No reaction is carried out with benzyl bromide.

[0348] R_(f) value: 0.40 (silica gel, methylene chloride/methanol/aceticacid=90:10:1)

[0349] Mass spectrum (ESI⁻): m/z=381 [M−H]⁻

EXAMPLE VII

[0350]4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(tert.-butyloxycarbonylamino)-ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[0351] A mixture of 410 mg4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-dihydrochloride,240 mg N-(tert.-butyloxycarbonyl)-2-bromo-ethylamine and 360 mgpotassium carbonate in 5 ml N,N-dimethylformamide is stirred overnightat ambient temperature. Then a further 80 mg ofN-(tert.-butyloxycarbonyl)-2-bromo-ethylamine are added and the reactionmixture is stirred for a further four hours at ambient temperature. Forworking up it is diluted with water and extracted with ethyl acetate.The combined organic phases are washed with saturated sodium chloridesolution, dried over magnesium sulphate and evaporated. The residue ischromatographed through a silica gel column with ethyl acetate/methanol(95:5 to 90:1) as eluant.

[0352] Yield: 370 mg (79% of theory)

[0353] R_(f) value: 0.33 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0354] Mass spectrum (ESI⁻): m/z=544, 546 [M−H]⁻

[0355] The following compound is obtained analogously to Example VII:

[0356] (1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(tert.-butyloxycarbonylamino)-ethyl]-piperidin-4-yloxy}-quinazoline

[0357] R_(f) value: 0.38 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0358] Mass spectrum (ESI⁺): m/z=516, 518 [M+H]⁺

EXAMPLE VIII

[0359]4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-dihydrochloride

[0360] Prepared by treating4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazolinewith concentrated hydrochloric acid in dioxane at ambient temperature.

[0361] R_(f) value: 0.53 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0362] Mass spectrum (ESI⁺): m/z=403, 405 [M+H]⁺

[0363] The following compounds are obtained analogously to AnalogExample VII:

[0364] (1) 6-(piperidin-4-yloxy)-3H-quinazolin-4-one x 2 TrifluoroaceticAcid

[0365] Carried out with trifluoroacetic acid in methylene chloride.

[0366] Mass spectrum (ESI⁺): m/z=246 [M+H]⁺

[0367] (2) 6-(piperidin-4-yloxy)-7-hydroxy-3H-quinazolin-4-one

[0368] Carried out with trifluoroacetic acid in methylene chloride.

[0369] R_(f) value: 0.60 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0370] Mass spectrum (ESI⁺): m/z=262 [M+H]⁺

EXAMPLE IX

[0371]4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

[0372] A solution of 7.80 ml diethyl azodicarboxylate in 100 mlmethylene chloride is added dropwise to a mixture of 10.00 g4-[(3-chloro-4-fluoro-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline and9.40 g 1-(tert.-butyloxycarbonyl)-4-hydroxy-piperidine and 12.40 gtriphenylphosphine in 400 ml methylene chloride at ambient temperature.The suspension is stirred for three days at ambient temperature and thensuction filtered. The filtrate is evaporated and chromatographed througha silica gel column with methylene chloride/methanol (98:2 auf 95:5) aseluant. The crude product obtained is combined with diisopropylether,stirred overnight therein, suction filtered and dried.

[0373] Yield: 5.34 g (34% of theory)

[0374] R_(f) value: 0.46 (silica gel, ethyl acetate/methanol=9:1)

[0375] Mass spectrum (ESI⁺): m/z=503, 505 [M+H]⁺

EXAMPLE X

[0376]4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(4-bromo-butyloxy)-quinazoline

[0377] A mixture of 500 mg4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-hydroxy-quinazoline,165 μl 1-bromo-4-chloro-propane and 360 mg potassium carbonate in 5 mlN,N-dimethylformamide is stirred overnight at 80° C. For working up thereaction mixture is diluted with water and extracted with ethyl acetate.The combined organic phases are washed with saturated sodium chloridesolution, dried over magnesium sulphate and evaporated. The crudeproduct is further reacted without any more purification.

[0378] Yield: 650 mg (97% of theory)

[0379] The following compounds are obtained analogously to Example X:

[0380] (1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-(4-bromo-butyloxy)-quinazoline

[0381] R_(f) value: 0.84 (silica gel, ethyl acetate/methanol=9:1)

[0382] (2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-ethoxy-quinazoline

[0383] Mass spectrum (ESI⁺): m/z=513, 515 [M+H]⁺

[0384] (3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline

[0385] R_(f) value: 0.38 (silica gel, methylene chloride/methanol=9:1)

[0386] Mass spectrum (ESI⁺): m/z=543, 545 [M+H]⁺

EXAMPLE XI

[0387] 1-(2-hydroxy-ethyl)-3-methyl-tetrahydropyrimidin-2-on

[0388] Prepared by hydrogenolytically cleaving1-(2-benzyloxy-ethyl)-3-methyl-tetrahydropyrimidin-2-one in the presenceof palladium on activated charcoal in methanol at ambient temperature.

[0389] R_(f) value: 0.23 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0390] Mass spectrum (ESI⁺): m/z=159 [M+H]⁺

EXAMPLE XII

[0391] 1-(2-benzyloxy-ethyl)-3-methyl-tetrahydropyrimidin-2-on

[0392] Prepared by reacting1-(2-benzyloxy-ethyl)-tetrahydropyrimidin-2-one with methyl iodide inthe presence of potassium-tert.-butoxide in N,N-dimethylformamide atambient temperature.

[0393] R_(f) value: 0.62 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0394] Mass spectrum (ESI⁺): m/z=249 [M+H]⁺

EXAMPLE XIII

[0395] 1-(2-benzyloxy-ethyl)-tetrahydropyrimidin-2-on

[0396] Prepared by treating1-(2-benzyloxy-ethyl)-3-(3-chloropropyl)-urea withpotassium-tert.-butoxide in N,N-dimethylformamide at ambienttemperature.

[0397] R_(f) value: 0.42 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0398] Mass spectrum (ESI⁺): m/z=235 [M+H]⁺

EXAMPLE XIV

[0399] 1-(2-benzyloxy-ethyl)-tetrahydropyrimidin-2-one

[0400] Prepared by reacting 2-benzyloxy-ethylamine with3-chloropropyl-isocyanate in tetrahydrofuran.

[0401] R_(f) value: 0.73 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0402] Mass spectrum (ESI⁺): m/z=271, 273 [M+H]⁺

EXAMPLE XV

[0403] 3-(tert.-butyloxycarbonylamino)-cyclohexanol

[0404] Prepared by reacting 3-amino-cyclohexanol with di-tert.butylpyrocarbonate in the presence of triethylamine in a mixture ofdioxan/water (2:1) at 50° C.

[0405] R_(f) value: 0.34 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=90:10:1)

[0406] Mass spectrum (ESI⁻): m/z=214 [M−H]⁻

[0407] The following compounds are obtained analogously to Example XV:

[0408] (1)cis-4-[(N-(tert.-butyloxycarbonyl)-N-methyl-amino]-cyclohexanol

[0409] The reaction takes place in methanol.

[0410] R_(f) value: 0.70 (silica gel, ethyl acetate)

[0411] Mass spectrum (ESI⁺): m/z=230 [M+H]⁺

EXAMPLE XVI

[0412] 6-(1-trifluoroacetyl-piperidin-4-yloxy)-3H-quinazolin-4-one

[0413] Prepared by reacting 6-(piperidin-4-yloxy)-3H-quinazolin-4-one x2 trifluoroacetic acid with trifluoroacetic acid anhydride in thepresence of triethylamine in tetrahydrofuran.

[0414] R_(f) value: 0.48 (silica gel, ethyl acetate/methanol=9:1)

[0415] Mass spectrum (ESI⁺): m/z=342 [M+H]⁺

[0416] The following compounds are obtained analogously to Example XVI:

[0417] (1)6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-hydroxy-3H-quinazolin-4-one

[0418] Carried out with methyl trifluoroacetate in the presence of Hunigbase in methanol.

[0419] R_(f) value: 0.80 (silica gel, methylene chloride/methanol=4:1)

[0420] Mass spectrum (ESI⁺): m/z=358 [M+H]⁺

EXAMPLE XVII

[0421] 2-nitro-5-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-benzoicAcid

[0422] 21.00 g potassium-tert.-butoxide are added batchwise to 25.14 g1-(tert.-butyloxycarbonyl)-piperidin-4-ol in 120 mlN,N-dimethylformamide while cooling with an ice bath, while thetemperature is kept below 10° C. The mixture is stirred for a further 30minutes while cooling with an ice bath, then 11.60 g of5-fluoro-2-nitro-benzoic acid are added. After another three hours thereaction mixture is poured onto water, adjusted to pH 1 with conc.hydrochloric acid and extracted with ethyl acetate. The combined organicphases are washed with dilute citric acid solution, dried over magnesiumsulphate and evaporated. The residue is triturated with diethyl ether,suction filtered and dried. More product crystallises out of thefiltrate after standing for some time, and this is also suction filteredand dried.

[0423] Yield: 9.58 g (42% of theory)

[0424] R_(f) value: 0.43 (silica gel, methylene chloride/methanol/aceticacid=90:10:1)

[0425] Mass spectrum (ESI⁺): m/z=367[M+H]⁺

EXAMPLE XVIII

[0426]4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-bromacetyl-piperidin-4-yloxy)-quinazolineand4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-chloracetyl-piperidin-4-yloxy)-quinazoline

[0427] Prepared by reacting4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-quinazolinewith bromoacetic acid chloride in the presence of Honig base intetrahydrofuran at ambient temperature. A mixture of the bromine andchlorine compounds is obtained.

[0428] R_(f) value: 0.43 (silica gel, methylene chloride/methanol=9:1)

[0429] Mass spectrum (ESI⁺): m/z=493, 495, 497 [M1+H]⁺ and 449, 451, 453[M2+H]⁺

[0430] The following compounds are obtained analogously to ExampleXVIII:

[0431] (1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-chloracetyl-piperidin-4-yloxy)-7-methoxy-quinazoline

[0432] The reaction takes place with chloroacetyl chloride.

[0433] R_(f) value: 0.59 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0434] Mass spectrum (ESI⁻): m/z=477, 479, 481 [M−H]⁻

EXAMPLE XIX

[0435]1-methyl-3-[([1,4]oxazepan-4-yl)carbonyl]-3H-imidazol-1-ium-iodide

[0436] Prepared by reacting3-[([1,4]oxazepan-4-yl)carbonyl]-3H-imidazole with methyl iodide inacetonitrile at ambient temperature. The crude product is reactedfurther without any more purification.

[0437] The following compounds are obtained analogously to Example XIX:

[0438] (1)1-methyl-3-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-3H-imidazol-1-ium-iodide

[0439] R_(f) value: 0.12 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0440] (2)1-methyl-3-[(2-methyl-morpholin-4-yl)carbonyl]-3H-imidazol-1-ium-iodide

[0441] R_(f) value: 0.02 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0442] (3)1-methyl-3-[(S,S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)carbonyl]-3H-imidazol-1-ium-iodide

[0443] R_(f) value: 0.01 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0444] (4)1-methyl-3-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-3H-imidazol-1-ium-iodide

[0445] R_(f) value: 0.03 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0446] (5)1-methyl-3-[(N-methyl-N-3-methoxypropyl-amino)carbonyl]-3H-imidazol-1-ium-iodide

[0447] R_(f) value: 0.12 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

EXAMPLE XX

[0448] 3-[([1,4]oxazepan-4-yl)carbonyl]-3H-imidazole

[0449] Prepared by reacting [1,4]oxazepan with N,N′-carbonyldiimidazolein the presence of triethylamine in tetrahydrofuran at ambienttemperature.

[0450] R_(f) value: 0.30 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0451] Mass spectrum (ESI⁺): m/z=196 [M+H]⁺

[0452] The following compounds are obtained analogously to Example XX:

[0453] (1) 3-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-3H-imidazole

[0454] R_(f) value: 0.46 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0455] (2) 3-[(2-methyl-morpholin-4-yl)carbonyl]-3H-imidazole

[0456] R_(f) value: 0.43 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0457] (3) 3-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)carbonyl]-3H-imidazole

[0458] R_(f) value: 0.59 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0459] (4) 3-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-3H-imidazole

[0460] R_(f) value: 0.32 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0461] (5) 3-[(N-methyl-N-3-methoxypropyl-amino)carbonyl]-3H-imidazole

[0462] R_(f) value: 0.36 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

EXAMPLE XXI

[0463]4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-hydroxy-quinazoline

[0464] Prepared by treating4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-acetoxy-quinazoline-hydrochloridewith saturated sodium hydrogen carbonate solution in methanol at ambienttemperature. In addition to the desired product, some4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-hydroxy-quinazolineis also isolated as a by-product.

[0465] R_(f) value: 0.20 (silica gel, methylene chloride/methanol=20:1)

[0466] Mass spectrum (ESI⁻): m/z=483, 485 [M−H]⁻

[0467] The following compounds are obtained analogously to Example XXI:

[0468] (1) 4-[(3-ethynyl-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline

[0469] Carried out with 40% sodium hydroxide solution in ethanol.

[0470] R_(f) value: 0.32 (silica gel, ethyl acetate)

[0471] Mass spectrum (ESI⁺): m/z=292 [M+H]⁺

[0472] (2)4-({3-chloro-4-[(3-fluorobenzyl)oxy]-phenyl}amino)-6-hydroxy-7-methoxy-quinazoline

[0473] R_(f) value: 0.70 (silica gel, methylene chloride/methanol=9:1)

[0474] Mass spectrum (ESI⁻): m/z=424, 426 [M−H]⁻

[0475] (3) 4-{[3-methyl-4-(pyridin-3-yloxy)phenyl}amino)-6-hydroxy-7-methoxy-quinazoline

[0476] R_(f) value: 0.23 (silica gel, methylene chloride/methanol=9:1)

[0477] Mass spectrum (ESI⁻): m/z=373 [M−H]⁻

EXAMPLE XXII

[0478]6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-acetoxy-3H-quinazolin-4-one

[0479] Prepared by reacting6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-hydroxy-3H-quinazolin-4-onewith acetic anhydride in pyridine at 80° C.

[0480] R_(f) value: 0.60 (silica gel, methylene chloride/methanol=9:1)

[0481] Mass spectrum (ESI⁺): m/z=400 [M+H]⁺

EXAMPLE XXIII

[0482]4-[(3-Chloro-4-fluorophenyl)amino]-6-{1-[(4-nitrophenyloxy)-carbonyl]-piperidin-4-vioxy}-7-methoxy-quinazoline

[0483] Prepared by reacting4-[(3-chloro-4-fluorophenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline(Example 2(2)) with (4-nitrophenyl) chloroformate.

[0484] R_(f) value: 0.48 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=90:10:1)

[0485] Preparation of the End Compounds:

EXAMPLE 1

[0486]4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-methoxy-quinazoline

[0487] 300 mg of4-[(3-chloro-4-fluoro-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline in 6ml acetonitrile are combined with 114 μl (R)-3-hydroxy-tetrahydrofuranand 370 mg triphenylphosphine. Then 234 μl diethyl azodicarboxylate areadded and the reaction mixture is stirred overnight at ambienttemperature. For working up the reaction mixture is filtered and thefiltrate evaporated down in vacuo. The crude product is purified bychromatography over a silica gel column with ethyl acetate/methanol(95:5) as eluant.

[0488] Yield: 53 mg (15% of theory)

[0489] melting point: 178° C.

[0490] Mass spectrum (ESI⁺): m/z=390, 392 [M+H]⁺

[0491] The following compounds are obtained analogously to Example 1:

[0492] (1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-methoxy-quinazoline

[0493] R_(f) value: 0.54 (silica gel, ethyl acetate/methanol=9:1)

[0494] Mass spectrum (ESI⁺): m/z=404, 406 [M+H]⁺

[0495] (2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(tert.-butyloxycarbonylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

[0496] R_(f) value: 0.70 (silica gel, ethyl acetate/methanol=9:1)

[0497] Mass spectrum (ESI⁺): m/z=517, 519 [M+H]⁺

[0498] (3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((R)-tetrahydrofuran-3-yloxy)-7-methoxy-quinazoline

[0499] R_(f) value: 0.64 (silica gel, ethyl acetate/methanol=9:1)

[0500] Mass spectrum (ESI⁺): m/z=390, 392 [M+H]⁺

[0501] (4)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(tert.-butyloxycarbonylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

[0502] R_(f) value: 0.65 (silica gel, ethyl acetate/methanol=9:1)

[0503] Mass spectrum (ESI⁺): m/z=517, 519 [M+H]⁺

[0504] (5)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

[0505] melting point: 184° C.

[0506] Mass spectrum (ESI⁺): m/z=503, 505 [M+H]⁺

[0507] (6)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline

[0508] R_(f) value: 0.52 (silica gel, methylene chloride/methanol=9:1)

[0509] Mass spectrum (ESI⁺): m/z=404, 406 [M+H]⁺

[0510] (7)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline

[0511] melting point: 218° C.

[0512] Mass spectrum (ESI⁺): m/z=417, 419 [M+H]⁺

[0513] (8)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(S)-1-(tert.-butyloxycarbonyl)-pyrrolidin-3-yloxy]-7-methoxy-quinazoline

[0514] Carried out with diisopropyl azodicarboxylate in methylenechloride.

[0515] R_(f) value: 0.51 (silica gel, methylene chloride/methanol=9:1)

[0516] Mass spectrum (ESI⁺): m/z=489, 491 [M+H]⁺

[0517] (9)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-3-yloxy]-7-methoxy-quinazoline

[0518] Carried out with diisopropyl azodicarboxylate in methylenechloride.

[0519] R_(f) value: 0.56 (silica gel, methylene chloride/methanol=9:1)

[0520] Mass spectrum (ESI⁻): m/z=501, 503 [M−H]⁻

[0521] (10)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-[2-(3-methyl-2-oxo-hexahydropyrimidin-1-yl)-ethoxy]-quinazoline

[0522] Carried out with diisopropyl azodicarboxylate in methylenechloride.

[0523] melting point: 235° C.

[0524] Mass spectrum (ESI⁺): m/z=516, 518 [M+H]⁺

[0525] (11)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(tert.-butyloxycarbonylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

[0526] Carried out with diisopropyl azodicarboxylate in methylenechloride.

[0527] R_(f) value: 0.68 (silica gel, ethyl acetate/methanol=9:1)

[0528] Mass spectrum (ESI⁻): m/z=515, 517 [M−H]⁻

[0529] (12)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(tert.-butyloxycarbonyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

[0530] Carried out with diisopropyl azodicarboxylate in methylenechloride.

[0531] R_(f) value: 0.37 (silica gel, methylene chloride/methanol=9:1)

[0532] Mass spectrum (ESI⁺): m/z=531, 533 [M+H]⁺

[0533] (13)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[N-(tert.-butyloxycarbonyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

[0534] Carried out with diisopropyl azodicarboxylate in methylenechloride.

[0535] melting point: 231° C.

[0536] Mass spectrum (ESI⁺): m/z=531, 533 [M+H]⁺

EXAMPLE 2

[0537]4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazolinex Trifluoroacetic Acid

[0538] Prepared by treating4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(tert.-butyloxycarbonylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazolinewith trifluoroacetic acid in methylene chloride at ambient temperature.

[0539] melting point: 221° C.

[0540] Mass spectrum (ESI⁺): m/z=417, 419 [M+H]⁺

[0541] The following compounds are obtained analogously to Example 2:

[0542] (1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[0543] Mass spectrum (ESI⁺): m/z=417, 419 [M+H]⁺

[0544] (2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazolinex Trifluoroacetic Acid

[0545] melting point: 232° C.

[0546] Mass spectrum (ESI⁺): m/z=403, 405 [M+H]⁺

EXAMPLE 3

[0547]4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[0548] Prepared by reacting4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazolinex trifluoroacetic acid with methanesulphonic acid chloride in thepresence of Hunig base in tetrahydrofuran at ambient temperature.

[0549] R_(f) value: 0.77 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=40:10:1)

[0550] Mass spectrum (ESI⁺): m/z=495, 497 [M+H]⁺

[0551] The following compounds are obtained analogously to Example 3:

[0552] (1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[0553] R_(f) value: 0.20 (silica gel, ethyl acetate)

[0554] Mass spectrum (ESI⁺): m/z=495, 497 [M+H]⁺

[0555] (2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline

[0556] R_(f) value: 0.59 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0557] Mass spectrum (ESI⁺): m/z=481, 483 [M+H]⁺

[0558] (3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(3-chloropropyl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

[0559] The reaction takes place with 3-chloropropansulphonyl chloride.

[0560] R_(f) value: 0.79 (silica gel, ethyl acetate/methanol=9:1)

[0561] Mass spectrum (ESI⁻): m/z=555, 557, 559 [M−H]⁻

[0562] (4)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(3-chloropropyl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

[0563] The reaction takes place with 3-chloropropanesulphonyl chloride.

[0564] R_(f) value: 0.42 (silica gel, ethyl acetate)

[0565] Mass spectrum (ESI⁺): m/z=557, 559, 561 [M+H]⁺

[0566] (5)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methylcarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline

[0567] The reaction takes place with acetic anhydride.

[0568] melting point: 216° C.

[0569] Mass spectrum (ESI⁺): m/z=445, 447 [M+H]⁺

[0570] (6)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[0571] The reaction takes place with N,N-dimethylcarbamoylchloride.

[0572] R_(f) value: 0.28 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0573] Mass spectrum (ESI⁺): m/z=474, 476 [M+H]⁺

[0574] (7)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[0575] The reaction takes place with (morpholin-4-yl)carbonylchloride inacetonitrile.

[0576] R_(f) value: 0.37 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0577] Mass spectrum (ESI⁺): m/z=516, 518 [M+H]⁺

[0578] (8)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[0579] The reaction takes place with methoxyacetic acid chloride.

[0580] R_(f) value: 0.80 (silica gel, methylene chloride/methanol=9:1)

[0581] Mass spectrum (ESI⁺): m/z=475, 477 [M+H]⁺

[0582] (9)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline

[0583] The reaction takes place with bromocyanogen in methylenechloride.

[0584] R_(f) value: 0.40 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0585] Mass spectrum (ESI⁺): m/z=428, 430 [M+H]⁺

[0586] (10)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)sulphonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[0587] The reaction takes place with N,N-dimethylsulphamoylchloride inacetonitrile.

[0588] R_(f) value: 0.24 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0589] Mass spectrum (ESI⁺): m/z=510, 512 [M+H]⁺

[0590] (11)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)sulphonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[0591] The reaction takes place with (morpholin-4-yl)sulphonyl chloridein acetonitrile.

[0592] R_(f) value: 0.29 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0593] Mass spectrum (ESI⁺): m/z=552, 554 [M+H]⁺

[0594] (12)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-3-yloxy)-7-methoxy-quinazoline

[0595] R_(f) value: 0.33 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroaceticacid=50:50:1)

[0596] Mass spectrum (ESI⁺): m/z=481, 483 [M+H]⁺

[0597] (13)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-1-methanesulphonyl-pyrrolidin-3-yloxy)-7-methoxy-quinazoline

[0598] melting point: 249° C.

[0599] Mass spectrum (ESI⁺): m/z=467, 469 [M+H]⁺

[0600] (14)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methanesulphonylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

[0601] R_(f) value: 0.49 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0602] Mass spectrum (ESI⁺): m/z=524, 526 [M+H]⁺

[0603] (15)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

[0604] The reaction takes place with acetic anhydride.

[0605] R_(f) value: 0.51 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0606] Mass spectrum (ESI⁺): m/z=488, 490 [M+H]⁺

[0607] (16)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

[0608] The reaction takes place with N,N-dimethylsulphamoylchloride inacetonitrile.

[0609] R_(f) value: 0.69 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0610] Mass spectrum (ESI⁺): m/z=524, 526 [M+H]⁺

[0611] (17)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

[0612] The reaction takes place with (morpholin-4-yl)carbonylchloride inacetonitrile.

[0613] R_(f) value: 0.38 (silica gel, ethyl acetate/methanol=9:1)

[0614] Mass spectrum (ESI⁺): m/z=530, 532 [M+H]⁺

[0615] (18)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

[0616] The reaction takes place with (morpholin-4-yl)sulphonyl chloridein acetonitrile.

[0617] melting point: 237° C.

[0618] Mass spectrum (ESI⁻): m/z=564, 566 [M−H]⁻

[0619] (19)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(3-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[0620] R_(f) value: 0.66 (silica gel, ethyl acetate/methanol=9:1)

[0621] Mass spectrum (ESI⁻): m/z=493, 495 [M−H]⁻

[0622] (20)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline

[0623] The reaction takes place with acetylchloride in acetonitrile.

[0624] melting point: 224° C.

[0625] Mass spectrum (ESI⁺): m/z=475, 477 [M+H]⁺

[0626] (21)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline

[0627] melting point: 227° C.

[0628] Mass spectrum (ESI⁺): m/z=511, 513 [M+H]⁺

[0629] (22)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-3-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[0630] The reaction takes place with acetylchloride in acetonitrile.Cis- and trans-isomer are separated by chromatography over a silica gelcolumn.

[0631] R_(f) value: 0.43 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=90:10:1)

[0632] Mass spectrum (ESI⁺): m/z=459, 461 [M+H]⁺

[0633] (23)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-3-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[0634] The reaction takes place with acetylchloride in acetonitrile.Cis- and trans-isomer are separated by chromatography over a silica gelcolumn.

[0635] R_(f) value: 0.49 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=90:10:1)

[0636] Mass spectrum (ESI⁺): m/z=459, 461 [M+H]⁺

[0637] (24)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(3-acetylamino-propyloxy)-quinazoline

[0638] The reaction takes place with acetylchloride.

[0639] melting point: 225° C.

[0640] Mass spectrum (ESI⁺): m/z=489, 491 [M+H]⁺

[0641] (25)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(3-methanesulphonylamino-propyloxy)-quinazoline

[0642] melting point: 222° C.

[0643] Mass spectrum (ESI⁺): m/z=525, 527 [M+H]⁺

[0644] (26)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-quinazoline

[0645] R_(f) value: 0.44 (silica gel, methylene chloride/methanol=9:1)

[0646] Mass spectrum (ESI⁺): m/z=451, 453 [M+H]⁺

[0647] (27)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-quinazoline

[0648] The reaction takes place with (morpholin-4-yl)carbonylchloride inacetonitrile.

[0649] R_(f) value: 0.40 (silica gel, methylene chloride/methanol=9:1)

[0650] Mass spectrum (ESI⁺): m/z=486, 488 [M+H]⁺

[0651] (28)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-quinazoline

[0652] The reaction takes place with acetic anhydride.

[0653] R_(f) value: 0.50 (silica gel, methylene chloride/methanol=9:1)

[0654] Mass spectrum (ESI⁺): m/z=415, 417 [M+H]⁺

[0655] (29)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)carbonyl]-piperidin-4-yloxy}-quinazoline

[0656] The reaction takes place with N,N-dimethylcarbamoylchloride.

[0657] R_(f) value: 0.47 (silica gel, methylene chloride/methanol=9:1)

[0658] Mass spectrum (ESI⁺): m/z=444, 446 [M+H]⁺

[0659] (30)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-acetylamino-cyclohexan-1-yloxy}-7-methoxy-quinazoline

[0660] The reaction takes place with acetic anhydride.

[0661] R_(f) value: 0.50 (silica gel, methylene chloride/methanol=9:1)

[0662] Mass spectrum (ESI⁺): m/z=459, 461 [M+H]⁺

[0663] (31)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

[0664] The reaction takes place with N,N-dimethylcarbamoylchloride.

[0665] R_(f) value: 0.40 (silica gel, methylene chloride/methanol=9:1)

[0666] Mass spectrum (ESI⁺): m/z=488, 490 [M+H]⁺

[0667] (32)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(2-methoxy-acetylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

[0668] The reaction takes place with methoxyacetic acid chloride.

[0669] R_(f) value: 0.35 (silica gel, methylene chloride/methanol=9:1)

[0670] Mass spectrum (ESI⁺): m/z=489, 491 [M+H]⁺

[0671] (33)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-quinazoline

[0672] The reaction takes place with methoxyacetic acid chloride.

[0673] R_(f) value: 0.41 (silica gel, methylene chloride/methanol=9:1)

[0674] Mass spectrum (ESI⁺): m/z=445, 447 [M+H]⁺

[0675] (34)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline

[0676] The reaction takes place with isopropyl chloroformate.

[0677] R_(f) value: 0.67 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=98:2:1)

[0678] Mass spectrum (ESI⁺): m/z=489, 491 [M+H]⁺

[0679] (35)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-quinazoline

[0680] The reaction takes place with bromocyanogen in methylenechloride.

[0681] R_(f) value: 0.49 (silica gel, methylene chloride/methanol 9:1)

[0682] Mass spectrum (ESI⁻): m/z=396, 398 [M−H]⁻

[0683] (36)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)sulphonyl]-piperidin-4-yloxy}-quinazoline

[0684] The reaction takes place with N,N-dimethylsulphamoylchloride inacetonitrile.

[0685] R_(f) value: 0.34 (silica gel, methylene chloride/methanol=9:1)

[0686] Mass spectrum (ESI⁺): m/z=480, 482 [M+H]⁺

[0687] (37)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)sulphonyl]-piperidin-4-yloxy}-quinazoline

[0688] The reaction takes place with (morpholin-4-yl)sulphonyl chloridein acetonitrile.

[0689] R_(f) value: 0.15 (silica gel, cyclohexane/ethyl acetate=1:1)

[0690] Mass spectrum (ESI⁺): m/z=522, 524 [M+H]⁺

[0691] (38)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-quinazoline

[0692] The reaction takes place with acetic anhydride in acetonitrile.

[0693] melting point: 221° C.

[0694] Mass spectrum (ESI⁺): m/z=458, 460 [M+H]⁺

[0695] (39)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(diethylamino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[0696] The reaction takes place with N,N-diethylcarbamoylchloride.

[0697] R_(f) value: 0.40 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=95:5:1)

[0698] Mass spectrum (ESI⁺): m/z=502, 504 [M+H]⁺

[0699] (40)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[0700] The reaction takes place with (piperidin-1-yl)carbonylchloride.

[0701] R_(f) value: 0.51 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=95:5:1)

[0702] Mass spectrum (ESI⁻): m/z=512, 514 [M−H]⁻

[0703] (41)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(pyrrolidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[0704] The reaction takes place with (pyrrolidin-1-yl)carbonylchloride.

[0705] melting point: 237° C.

[0706] Mass spectrum (ESI⁺): m/z=500, 502 [M+H]⁺

[0707] (42)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(4-methyl-piperazin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[0708] The reaction takes place with(4-methyl-piperazin-1-yl)carbonylchloride-hydrochloride.

[0709] R_(f) value: 0.28 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=90:10:1)

[0710] Mass spectrum (ESI⁻): m/z=527, 529 [M−H]⁻

[0711] (43)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

[0712] The reaction takes place in methylene chloride.

[0713] R_(f) value: 0.71 (silica gel, ethyl acetate/methanol=9:1)

[0714] Mass spectrum (ESI⁺): m/z=509, 511 [M+H]⁺

[0715] (44)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

[0716] The reaction takes place with acetic anhydride.

[0717] melting point: 234° C.

[0718] Mass spectrum (ESI⁺): m/z=473, 475 [M+H]⁺

[0719] (45)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

[0720] The reaction takes place with methoxyacetic acid chloride.

[0721] R_(f) value: 0.40 (silica gel, ethyl acetate/methanol=9:1)

[0722] Mass spectrum (ESI⁺): m/z=503, 505 [M+H]⁺

[0723] (46)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-dimethylaminocarbonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

[0724] The reaction takes place with N,N-dimethylcarbamoylchloride.

[0725] R_(f) value: 0.51 (silica gel, ethyl acetate/methanol=9:1)

[0726] Mass spectrum (ESI⁺): m/z=502, 504 [M+H]⁺

[0727] (47)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[0728] The reaction takes place with (morpholin-4-yl)carbonylchloride.

[0729] R_(f) value: 0.50 (silica gel, ethyl acetate/methanol=9:1)

[0730] Mass spectrum (ESI⁺): m/z=544, 546 [M+H]⁺

[0731] (48)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[0732] The reaction takes place with (morpholin-4-yl)sulphonyl chloridein acetonitrile.

[0733] R_(f) value: 0.24 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0734] Mass spectrum (ESI⁺): m/z=580, 582 [M+H]⁺

[0735] (49)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-dimethylaminosulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

[0736] The reaction takes place with N,N-dimethylsulphamoylchloride inacetonitrile.

[0737] R_(f) value: 0.53 (silica gel, ethyl acetate)

[0738] Mass spectrum (ESI⁺): m/z=538, 540 [M+H]⁺

[0739] (50)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[0740] The reaction takes place with ethanesulphonic acid chloride inmethylene chloride.

[0741] R_(f) value: 0.41 (silica gel, ethyl acetate)

[0742] Mass spectrum (ESI⁺): m/z=509, 511 [M+H]⁺

[0743] (51)4-[(3-chloro-4-fluoro-phenyl)amino]-6-1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-ethoxy-quinazoline

[0744] The reaction takes place with (morpholin-4-yl)carbonylchloride.

[0745] R_(f) value: 0.48 (silica gel, methylene chloride/methanol=9:1)

[0746] Mass spectrum (ESI⁺): m/z=530, 532 [M+H]⁺

[0747] (52)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline

[0748] R_(f) value: 0.50 (silica gel, methylene chloride/methanol=9:1)

[0749] Mass spectrum (ESI⁺): m/z=495, 497 [M+H]⁺

[0750] (53)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-ethoxy-quinazoline

[0751] The reaction takes place with methoxyacetic acid chloride.

[0752] R_(f) value: 0.40 (silica gel, methylene chloride/methanol=20:1)

[0753] Mass spectrum (ESI⁺): m/z=489, 491 [M+H]⁺

[0754] (54)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline

[0755] R_(f) value: 0.47 (silica gel, methylene chloride/methanol=9:1)

[0756] Mass spectrum (ESI⁺): m/z=525, 527 [M+H]⁺

[0757] (55)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline

[0758] The reaction takes place with (morpholin-4-yl)carbonylchloride.

[0759] R_(f) value: 0.48 (silica gel, methylene chloride/methanol=9:1)

[0760] Mass spectrum (ESI⁺): m/z=560, 562 [M+H]⁺

[0761] (56)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline

[0762] The reaction takes place with methoxyacetic acid chloride.

[0763] R_(f) value: 0.48 (silica gel, methylene chloride/methanol=9:1)

[0764] Mass spectrum (ESI⁺): m/z=519, 521 [M+H]⁺

[0765] (57)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[0766] The reaction takes place with acetic anhydride.

[0767] melting point: 281° C.

[0768] Mass spectrum (ESI⁺): m/z=459, 461 [M+H]⁺

[0769] (58)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-(2-methoxy-acetylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

[0770] The reaction takes place with methoxyacetic acid chloride.

[0771] melting point: 264° C.

[0772] Mass spectrum (ESI⁺): m/z=489, 491 [M+H]⁺

[0773] (59)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[0774] The reaction takes place with (piperidin-1-yl)carbonylchloride.

[0775] melting point: 253° C.

[0776] Mass spectrum (ESI⁺): m/z=542, 544 [M+H]⁺

[0777] (60)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[0778] The reaction takes place with(4-methyl-piperazin-1-yl)carbonylchloride-hydrochloride.

[0779] melting point: 262° C.

[0780] Mass spectrum (ESI⁺): m/z=557, 559 [M+H]⁺

[0781] (61)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-ethanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

[0782] The reaction takes place with ethanesulphonic acid chloride inmethylene chloride.

[0783] R_(f) value: 0.19 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0784] Mass spectrum (ESI⁺): m/z=523, 525 [M+H]⁺

[0785] (62)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

[0786] The reaction takes place with (morpholin-4-yl)carbonylchloride.

[0787] R_(f) value: 0.33 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0788] Mass spectrum (ESI⁺): m/z=530, 532 [M+H]⁺

[0789] (63)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

[0790] The reaction takes place with (morpholin-4-yl)sulphonyl chloridein acetonitrile.

[0791] R_(f) value: 0.81 (silica gel, ethyl acetate/methanol=9:1)

[0792] Mass spectrum (ESI⁺): m/z=566, 568 [M+H]⁺

[0793] (64)4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline

[0794] The reaction takes place with acetic anhydride.

[0795] R_(f) value: 0.30 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0796] Mass spectrum (ESI⁺): m/z=417 [M+H]⁺

[0797] (65)4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

[0798] The reaction takes place with methoxyacetic acid chloride.

[0799] R_(f) value: 0.37 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=90:10:1)

[0800] Mass spectrum (ESI⁺): m/z=447 [M+H]⁺

[0801] (66)4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline

[0802] R_(f) value: 0.59 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0803] Mass spectrum (ESI⁺): m/z=453 [M+H]⁺

[0804] (67)4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[0805] The reaction takes place with (morpholin-4-yl)carbonylchloride.

[0806] R_(f) value: 0.43 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0807] Mass spectrum (ESI⁺): m/z=488 [M+H]⁺

[0808] (68)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

[0809] R_(f) value: 0.50 (silica gel, methylene chloride/methanol=9:1)

[0810] Mass spectrum (ESI⁺): m/z=509, 511 [M+H]⁺

[0811] (69)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[0812] The reaction takes place with (morpholin-4-yl)carbonylchloride.

[0813] R_(f) value: 0.54 (silica gel, methylene chloride/methanol=9:1)

[0814] Mass spectrum (ESI⁺): m/z=544, 546 [M+H]⁺

[0815] (70)4-{[3-methyl-4-(pyridin-3-yloxy)-phenyl]amino)-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-methanesulphonate

[0816] R_(f) value: 0.58 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0817] Mass spectrum (ESI⁺): m/z=536 [M+H]⁺

[0818] (71)4-[(3-chloro-4-[(3-fluoro-benzyl)oxy]-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline

[0819] R_(f) value: 0.80 (silica gel, methylene chloride/methanol=9:1)

[0820] Mass spectrum (ESI⁺): m/z=587, 589 [M+H]⁺

EXAMPLE 4

[0821]4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{[3-(morpholin-4-yl)-propyl]sulphonylamino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[0822] 23 μl of morpholine are added to 60 mg of4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(3-chloropropyl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazolinein 2 ml acetonitrile and the reaction mixture is refluxed overnight. Forworking up the mixture is taken up in ethyl acetate and washed withwater. The organic phase is dried over magnesium sulphate and evaporateddown. The crude product is purified through a silica gel column withmethylene chloride/methanol (9:1) as eluant.

[0823] Yield: 18 mg (27% of theory)

[0824] R_(f) value: 0.36 (silica gel, methylene chloride/methanol=9:1)

[0825] Mass spectrum (ESI⁺): m/z=608, 610 [M+H]⁺

[0826] The following compounds are obtained analogously to Example 4:

[0827] (1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{[3-(morpholin-4-yl)-propyl]sulphonylamino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[0828] R_(f) value: 0.16 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0829] Mass spectrum (ESI⁺): m/z=608, 610 [M+H]⁺

[0830] (2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[4-(morpholin-4-yl)-butyloxy]-quinazoline

[0831] Carried out in the presence of sodium carbonate and sodium iodidein N-methylpyrrolidone at 100° C.

[0832] R_(f) value: 0.18 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=40:10:0.5)

[0833] Mass spectrum (ESI⁺): m/z=531, 533 [M+H]⁺

[0834] (3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-[4-(morpholin-4-yl)-butyloxy]-quinazoline

[0835] Carried out in the presence of sodium carbonate and sodium iodidein N-methylpyrrolidone at 100° C.

[0836] R_(f) value: 0.32 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=80:20:1)

[0837] Mass spectrum (ESI⁺): m/z=517, 519 [M+H]⁺

[0838] (4)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)acetyl]-piperidin-4-yloxy}-quinazoline

[0839] Carried out in the presence of Hunig base in tetrahydrofuran atambient temperature.

[0840] R_(f) value: 0.30 (silica gel, methylene chloride/methanol=9:1)

[0841] Mass spectrum (ESI⁺): m/z=500, 502 [M+H]⁺

[0842] (5)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-dimethylaminoacetyl-piperidin-4-yloxy)-quinazoline

[0843] Carried out in the presence of Hunig base in tetrahydrofuran atambient temperature.

[0844] R_(f) value: 0.11 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=90:10:1)

[0845] Mass spectrum (ESI⁺): m/z=458, 460 [M+H]⁺

[0846] (6)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-dimethylaminoacetyl-piperidin-4-yloxy)-7-methoxy-quinazoline

[0847] Carried out in the presence of Hunig base in tetrahydrofuran atambient temperature.

[0848] R_(f) value: 0.19 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0849] Mass spectrum (ESI⁺): m/z=488, 490 [M+H]⁺

[0850] (7)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)acetyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[0851] Carried out in the presence of Hunig base in tetrahydrofuran atambient temperature.

[0852] Mass spectrum (ESI⁺): m/z=530, 532 [M+H]⁺

EXAMPLE 5

[0853]4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-pyrrolidin-3-yloxy)-7-methoxy-quinazoline-dihydrochloride

[0854] A solution of 370 mg4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(S)-1-(tert.-butyloxy-carbonyl)-pyrrolidin-3-yloxy]-7-methoxy-quinazolinein 5 ml dioxane is combined with 0.32 ml concentrated hydrochloric acidand stirred overnight at ambient temperature. The precipitate formed issuction filtered and washed with copious amounts of dioxane. The crudeproduct is dissolved in a little methanol and re-precipitated by theaddition of the same amount of ethyl acetate. The white solid thusobtained is suction filtered and dried.

[0855] Yield: 200 mg (57% of theory)

[0856] melting point: 281° C.

[0857] Mass spectrum (ESI⁺): m/z=389, 391 [M+H]⁺

[0858] The following compounds are obtained analogously to Example 5:

[0859] (1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline-dihydrochloride

[0860] melting point: 263° C.

[0861] Mass spectrum (ESI⁺): m/z=403, 505 [M+H]⁺

[0862] (2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-amino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-dihydrochloride

[0863] melting point: 277° C.

[0864] Mass spectrum (ESI⁺): m/z=446, 448 [M+H]⁺

[0865] (3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(3-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-dihydrochloride

[0866] Mass spectrum (ESI⁺): m/z=417, 419 [M+H]⁺

[0867] (4)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-amino-ethoxy)-quinazoline-dihydrochloride

[0868] Carried out with isopropanolic hydrochloric acid (5-6 M) inmethylene chloride.

[0869] R_(f) value: 0.58 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0870] Mass spectrum (ESI⁺): m/z=433, 435 [M+H]⁺

[0871] (5)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(3-amino-propyloxy)-quinazoline-dihydrochloride

[0872] Carried out with isopropanolic hydrochloric acid (5-6 M) inmethylene chloride.

[0873] R_(f) value: 0.44 (Reversed phase ready-made TLC plate (E.Merck), methanol/5% aqueous sodium chloride solution=7:3)

[0874] Mass spectrum (ESI⁺): m/z=447, 449 [M+H]⁺

[0875] (6)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-amino-ethyl)-piperidin-4-yloxy]-quinazoline-dihydrochloride

[0876] R_(f) value: 0.50 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50: 1)

[0877] Mass spectrum (ESI⁺): m/z=416, 418 [M+H]⁺

[0878] (7)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-dihydrochloride

[0879] Carried out with isopropanolic hydrochloric acid (5-6 M) inmethylene chloride.

[0880] R_(f) value: 0.35 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0881] Mass spectrum (ESI⁺): m/z=431, 433 [M+H]⁺

[0882] (8)4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-dihydrochloride

[0883] Carried out with isopropanolic hydrochloric acid (5-6 M) inmethylene chloride.

[0884] R_(f) value: 0.50 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0885] Mass spectrum (ESI⁺): m/z=375 [M+H]⁺

[0886] (9)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-dihydrochloride

[0887] melting point: 251° C.

[0888] Mass spectrum (ESI⁺): m/z=431, 433 [M+H]⁺

[0889] (10)4-{[3-methyl-4-(pyridin-3-yloxy)-phenyl]amino)-6-(piperidin-4-yloxy)-7-methoxy-quinazolinedihydrochloride

[0890] R_(f) value: 0.50 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0891] Mass spectrum (ESI⁺): m/z=458 [M+H]⁺

[0892] (11)4-({3-chloro-4-[(3-fluorobenzyl)oxy]-phenyl}amino)-6-(piperidin-4-yloxy)-7-methoxy-quinazolinedihydrochloride

[0893] R_(f) value: 0.38 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0894] Mass spectrum (ESI⁺): m/z=507, 509 [M−H]⁻

[0895] (12)4-{[3-methyl-4-(pyridin-3-yloxy)-phenyl}amino)-6-(trans-4-aminocyclohexan-1-yloxy)-7-methoxy-quinazolinedihydrochloride

[0896] R_(f) value: 0.58 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0897] Mass spectrum (ESI⁺): m/z=472 [M+H]⁺

[0898] (13)4-({3-chloro-4-[(3-fluorobenzyl)oxy]-phenyl}amino)-6-(trans-4-aminocyclohexan-1-yloxy)-7-methoxy-quinazolineDihydrochloride

[0899] R_(f) value: 0.48 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0900] Mass spectrum (ESI⁺): m/z=523, 525 [M+H]⁺

EXAMPLE 6

[0901]4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-hydroxy-quinazoline

[0902] A mixture of 9.00 g4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-benzyloxy-quinazoline-hydrochlorideand 50 ml trifluoroacetic acid is heated to 100° C. for 1.5 hours. Thenthe reaction mixture is evaporated and the residue is taken up in 10 mlacetonitrile. This solution is added dropwise to 100 ml saturated sodiumhydrogen carbonate solution with vigorous stirring. After 1.5 hours theprecipitate formed is suction filtered and washed several times withwater. The crude product is stirred with diethyl ether, suction filteredand dried.

[0903] Yield: 5.90 g (87% of theory)

[0904] R_(f) value: 0.21 (silica gel, ethyl acetate)

[0905] Mass spectrum (ESI⁺): m/z=390, 392 [M+H]⁺

[0906] The following compounds are obtained analogously to Example 6:

[0907] (1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline

[0908] R_(f) value: 0.44 (silica gel, ethyl acetate/methanol=9:1)

[0909] Mass spectrum (ESI⁺): m/z=376, 378 [M+H]⁺

EXAMPLE 7

[0910]4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[3-(morpholin-4-yl)-propyloxy]-quinazoline

[0911] A mixture of 300 mg4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-hydroxy-quinazoline,130 mg 3-(morpholin-4-yl)-propylchloride and 530 mg potassium carbonatein 5 ml N,N-dimethylformamide is stirred overnight at 80° C. For workingup the reaction mixture is diluted with 25 ml of water and extractedwith ethyl acetate. The combined organic phases are washed withsaturated sodium chloride solution, dried over magnesium sulphate andevaporated. The residue is stirred with diethyl ether, suction filteredand dried.

[0912] Yield: 250 mg (63% of theory)

[0913] melting point: 205° C.

[0914] Mass spectrum (ESI⁺): m/z=517, 519 [M+H]⁺

[0915] The following compounds are obtained analogously to Example 7:

[0916] (1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[2-(morpholin-4-yl)-ethoxy]-quinazoline

[0917] R_(f) value: 0.33 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=40:10:0.5)

[0918] Mass spectrum (ESI⁺): m/z=503, 505 [M+H]⁺

[0919] (2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline

[0920] R_(f) value: 0.76 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0921] Mass spectrum (ESI⁺): m/z=418, 420 [M+H]⁺

[0922] (3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-[3-(morpholin-4-yl)-propyloxy]-quinazoline

[0923] R_(f) value: 0.20 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0924] Mass spectrum (ESI⁻): m/z=501, 503[M−H]⁻

[0925] (4)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-[2-(morpholin-4-yl)-ethoxy]-quinazoline

[0926] R_(f) value: 0.19 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0927] Mass spectrum (ESI⁺): m/z=489, 491 [M+H]⁺

[0928] (5)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline

[0929] R_(f) value: 0.57 (silica gel, methylene chloride/methanol=9:1)

[0930] Mass spectrum (ESI⁺): m/z=448, 450 [M+H]⁺

[0931] (6)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[2-(tert.-butyloxycarbonylamino)-ethoxy]-quinazoline

[0932] R_(f) value: 0.64 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=95:5:0.1)

[0933] Mass spectrum (ESI⁺): m/z=533, 535 [M+H]⁺

[0934] (7)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[3-(tert.-butyloxycarbonylamino)-propyloxy]-quinazoline

[0935] R_(f) value: 0.74 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=95:5:0.1)

[0936] Mass spectrum (ESI⁺): m/z=547, 549 [M+H]⁺

Example 8

[0937]4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-quinazoline

[0938] A solution of 4.55 g4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-quinazoline-hydrochloridein 35 ml methanol is combined with 13 ml (3 N) sodium hydroxide solutionand stirred for about half an hour at ambient temperature. For workingup the reaction mixture is diluted with water and extracted with ethylacetate. The combined organic phases are washed with saturated sodiumchloride solution, dried over magnesium sulphate and evaporated. Theresidue is stirred with diethyl ether, suction filtered and dried.

[0939] Yield: 3.00 g (89% of theory)

[0940] R_(f) value: 0.48 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0941] Mass spectrum (ESI⁺): m/z=373, 375 [M+H]⁺

[0942] The following compounds are obtained analogously to Example 8:

[0943] (1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-ethoxy-quinazoline

[0944] R_(f) value: 0.20 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=90:10:1)

[0945] Mass spectrum (ESI⁺): m/z=417, 419 [M+H]⁺

[0946] (2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline

[0947] R_(f) value: 0.10 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=90:10:1)

[0948] Mass spectrum (ESI⁺): m/z=447, 449 [M+H]⁺

EXAMPLE 9

[0949]4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(ethylamino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[0950] Prepared by reacting4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazolinewith ethyl isocyanate in tetrahydrofuran at ambient temperature.

[0951] R_(f) value: 0.53 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0952] Mass spectrum (ESI⁺): m/z=474, 476 [M+H]⁺

[0953] The following compounds are obtained analogously to Example 9:

[0954] (1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(isopropylamino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[0955] melting point: 236° C.

[0956] Mass spectrum (ESI⁻): m/z=486, 488 [M−H]⁻

[0957] (2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(phenylamino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[0958] R_(f) value: 0.70 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=95:5:0.1)

[0959] Mass spectrum (ESI⁺): m/z=522, 524 (M+H]⁺

[0960] (3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{(N-[(ethylamino)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[0961] R_(f) value: 0.38 (silica gel, methylene chloride/methanol=9:1)

[0962] Mass spectrum (ESI⁺): m/z=502, 504 [M+H]⁺

EXAMPLE 10

[0963]4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)carbonylmethyl]-piperidin-4-yloxy}-quinazoline

[0964] Prepared by reacting4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-quinazolinewith 2-chloro-N,N-dimethylacetamide in the presence of potassiumcarbonate in N,N-dimethylformamide at ambient temperature.

[0965] R_(f) value: 0.24 (silica gel, methylene chloride/methanol=9:1)

[0966] Mass spectrum (ESI⁺): m/z=458, 460 [M+H]⁺

[0967] The following compounds are obtained analogously to Example 10:

[0968] (1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonylmethyl]-piperidin-4-yloxy}-quinazoline

[0969] R_(f) value: 0.42 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[0970] Mass spectrum (ESI⁺): m/z=500, 502 [M+H]⁺

[0971] (2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline

[0972] melting point: 251° C.

[0973] Mass spectrum (ESI⁺): m/z=460, 462 [M+H]⁺

[0974] (3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)carbonylmethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[0975] melting point: 233° C.

[0976] Mass spectrum (ESI⁺): m/z=488, 490 [M+H]⁺

[0977] (4)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonylmethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[0978] melting point: 245° C.

[0979] Mass spectrum (ESI⁺): m/z=530, 532 [M+H]⁺

[0980] (5)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxyethyl)-piperidin-4-yloxy}-7-methoxy-quinazoline

[0981] melting point: 178° C.

[0982] Mass spectrum (ESI⁺): m/z=461, 463 [M+H]⁺

[0983] (6)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[0984] melting point: 234° C.

[0985] R_(f) value: 0.28 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=90:10:1)

[0986] Mass spectrum (ESI⁺): m/z=514, 516 [M+H]⁺

EXAMPLE 11

[0987]4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(tetrahydropyran-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[0988] 90 mg 1-hydroxy-1H-benzotriazole and 250 mg2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborateare added to a mixture of 300 mg4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-dihydrochloride,82 mg tetrahydropyran-4-carboxylic acid and 0.54 ml Hunig base in 5 mlN,N-dimethylformamide. The reaction mixture is stirred overnight atambient temperature. For working up it is combined with 25 ml ethylacetate and washed with water, 10% potassium carbonate solution andsaturated sodium chloride solution. The organic phase is dried overmagnesium sulphate and evaporated. The residue is stirred with a littleethyl acetate, suction filtered and dried.

[0989] Yield: 250 mg (77% of theory)

[0990] R_(f) value: 0.43 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0991] Mass spectrum (ESI⁺): m/z=515, 517 [M+H]⁺

[0992] The following compounds are obtained analogously to Example 11:

[0993] (1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(tetrahydropyran-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

[0994] R_(f) value: 0.44 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[0995] Mass spectrum (ESI⁺): m/z=529, 531 [M+H]⁺

[0996] (2)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[0997] R_(f) value: 0.31 (silica gel, ethyl acetate/methanol=9:1)

[0998] Mass spectrum (ESI⁺): m/z=543, 545 [M+H]⁺

[0999] (3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(R)-(tetrahydrofuran-2-yl)carbonyl]-piperidin-4-yloxy)-7-methoxy-quinazoline

[1000] Melting point: 243° C.

[1001] (4)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S)-(tetrahydrofuran-2-yl)carbonyl]-piperidin-4-yloxy)-7-methoxy-quinazoline

[1002] R_(f) value: 0.34 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia 90:10:1)

[1003] (5)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy)-7-methoxy-quinazoline

[1004] R_(f) value: 0.31 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=90:10:1)

[1005] Mass spectrum (ESI⁺): m/z=487, 489 [M−H]⁻

EXAMPLE 12

[1006]4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[([1,4]oxazepan-4-yl)carbonyl)-piperidin-4-yloxy}-7-methoxy-quinazoline

[1007]4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-dihydrochlorideand 1.05 ml triethylamine are added to 900 mg of1-methyl-3-[([1,4]oxazepan-4-yl)carbonyl]-3H-imidazol-1-ium-iodide in 10ml methylene chloride. The yellowish suspension is stirred for about 24hours at ambient temperature. For working up the reaction mixture iscombined with 50 ml methylene chloride and extracted with water as wellas 10% citric acid. The organic phase is washed with saturated sodiumchloride solution, dried over magnesium sulphate and evaporated down.The residue is chromatographed through a silica gel column withmethylene chloridelmethanol/conc. ammonia as eluant. The desired productis stirred with diethyl ether, suction filtered and dried.

[1008] Yield: 800 mg (80% of theory)

[1009] R_(f) value: 0.30 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=90:10:1)

[1010] Mass spectrum (ESI⁺): m/z=530, 532 [M+H]⁺

[1011] The following compounds are obtained analogously to Example 12:

[1012] (1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[1013] R_(f) value: 0.41 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[1014] Mass spectrum (ESI⁺): m/z=544, 546 [M+H]⁺

[1015] (2)4-((3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[1016] R_(f) value: 0.50 (silica gel, ethyl acetate/methanol/conc.aqueous ammonia=90:10:1)

[1017] Mass spectrum (ESI⁺): m/z=530, 532 [M+H]⁺

[1018] (3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)carbonyl]-piperidin-4-yloxy)-7-methoxy-quinazoline

[1019] Melting point: 193° C.

[1020] (4)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy)-7-methoxy-quinazoline

[1021] Melting point: 171° C.

[1022] (5)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-3-methoxypropyl-amino)carbonyl]-piperidin-4-yloxy)-7-methoxy-quinazoline

[1023] R_(f) value: 0.23 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=90:10:1)

[1024] Mass spectrum (ESI⁺): m/z=532, 534 [M+H]⁺

EXAMPLE 13

[1025]4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-ethoxy-quinazoline

[1026] 35 μl 37% aqueous formalin solution and 110 mg of sodiumtriacetoxyborohydride are added to 175 mg4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-ethoxy-quinazolinein 1 ml of tetrahydrofuran. The reaction mixture is stirred for aboutfour hours at ambient temperature. For working up 5 ml saturated sodiumhydrogen carbonate solution are added and the mixture is stirredthoroughly. Then 20 ml ethyl acetate are added and the aqueous phase isseparated off. The organic phase is washed with water and saturatedsodium chloride solution, dried over magnesium sulphate and evaporated.The residue is stirred with diisopropylether, suction filtered anddried.

[1027] Yield: 144 mg (80% of theory)

[1028] R_(f) value: 0.80 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=60:10:1)

[1029] Mass spectrum (ESI⁺): m/z=431, 433 [M+H]⁺

[1030] The following compounds are obtained analogously to Example 13:

[1031] (1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline

[1032] R_(f) value: 0.85 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=60:10:1)

[1033] Mass spectrum (ESI⁺): m/z=461, 463 [M+H]⁺

[1034] (2)4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline-hydrochloride

[1035] R_(f) value: 0.26 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=90:10:1)

[1036] Mass spectrum (ESI⁺): m/z=389 [M+H]⁺

[1037] (3)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[1038] R_(f) value: 0.80 (aluminium oxide, methylenechloride/methanol=9:1)

[1039] Mass spectrum (ESI⁺): m/z=445, 447 [M+H]⁺

[1040] (4)4-[(3-chloro-4-fluoro-phenyl)amino]-S-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazolineHydrochloride

[1041] Carried out with acetaldehyde

[1042] R_(f) value: 0.44 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[1043] Mass spectrum (ESI⁺): m/z=431, 433 [M+H]⁺

[1044] (5)4-{[3-methyl-4-(pyridin-3-yloxy)-phenyl)amino}-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline

[1045] R_(f) value: 0.68 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=60:10:1)

[1046] Mass spectrum (ESI⁺): m/z=472 [M+H]⁺

[1047] (6)4-({3-chloro-4-[(3-fluorobenzyl)oxy]-phenyl}amino)-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline

[1048] R_(f) value: 0.70 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=90:10:1)

[1049] Mass spectrum (ESI⁺): m/z=523, 525 [M+H]⁺

EXAMPLE 14

[1050]4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

[1051] A mixture of 3.00 g4-[(3-ethynyl-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline, 4.50 g1-(tert.-butyloxycarbonyl)-4-(p-toluolsulphonyloxy)-piperidin and 2.90 gpotassium carbonate in 30 ml N,N-dimethylformamide is stirred for twodays at 60° C. For working up the mixture is combined with 200 ml ethylacetate and extracted with water. The organic phase is washed withsaturated sodium chloride solution, dried over magnesium sulphate andevaporated. The crude product is purified over a silica gel column withmethylene chloride/methanol/conc. ammonia as eluant.

[1052] Yield: 3.25 g (67% of theory)

[1053] R_(f) value: 0.25 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=95:5:1)

[1054] Mass spectrum (ESI⁺): m/z=475 [M+H]⁺

[1055] The following compounds are obtained analogously to Example 14:

[1056] (1)4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline

[1057] R_(f) value: 0.40 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=90:10:1)

[1058] Mass spectrum (ESI⁺): m/z=376 [M+H]⁺

[1059] (2)4-({3-chloro-4-[(3-fluorobenzyl)oxy]-phenyl}amino)-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline

[1060] R_(f) value: 0.32 (silica gel, methylene chloride/methanol=20:1)

[1061] Mass spectrum (ESI⁺): m/z=510, 512 [M+H]⁺

[1062] (3)4-{[3-methyl-4-(pyridin-3-yloxy)-phenyl)amino}-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline

[1063] R_(f) value: 0.55 (silica gel, methylene chloride/methanol=9:1)

[1064] Mass spectrum (ESI⁺): m/z=459 [M+H]⁺

[1065] (4)4-{[3-methyl-4-(pyridin-3-yloxy)-phenyl)amino}-6-(1-tert.butyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline

[1066] R_(f) value: 0.40 (silica gel, methylene chloride/methanol=9:1)

[1067] Mass spectrum (ESI⁺): m/z=558 [M+H]⁺

[1068] (5) 4-({3-chloro-4-[(3-fluorobenzyl)oxy]-phenyl)amino}-6-(1-tert.butyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline

[1069] R_(f) value: 0.65 (silica gel, methylene chloride/methanol=9:1)

[1070] Mass spectrum (ESI⁺): m/z=609, 611 [M+H]⁺

[1071] (6)4-{[3-methyl-4-(pyridin-3-yloxy)-phenyl)amino}-6-[trans-4-(tert.butyloxycarbonylamino)-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[1072] The alkylating agent used,cis-4-(tert.butyloxycarbonylamino)-1-(4-methylphenylsulphonyloxy)-cyclohexane(mass spectrum (ESI⁺): m/z=370 [M+H]⁺) was prepared by reactingcis-4-(tert.butyloxycarbonylamino)-cyclohexanol with4-methylphenyl-sulphonyl chloride in pyridine.

[1073] Mass spectrum (ESI⁺): m/z=572 [M+H]⁺

[1074] (7)4-({3-chloro-4-[(3-fluorobenzyl)oxy]-phenyl}amino)-6-[trans-4-(tert.butyloxycarbonylamino)-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[1075] The alkylating agent used,cis-4-(tert.butyloxycarbonylamino)-1-(4-methylphenylsulphonyloxy)-cyclohexane(mass spectrum (ESI⁺): m/z=370 [M+H]⁺) was prepared by reactingcis-4-(tert.butyloxycarbonylamino)-cyclohexanol with4-methylphenyl-sulphonyl chloride in pyridine.

[1076] Mass spectrum (ESI⁺): m/z=623, 625 [M+H]⁺

EXAMPLE 15

[1077]4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(tert.-butyloxycarbonylamino)-ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[1078] A mixture of 410 mg of4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-dihydrochloride,240 mg of N-(tert.-butyloxycarbonyl)-2-bromo-ethylamine and 360 mg ofpotassium carbonate in 5 ml N,N-dimethylformamide is stirred overnightat ambient temperature. Then another 80 mgN-(tert.-butyloxycarbonyl)-2-bromo-ethylamine are added and the reactionmixture is stirred for a further four hours at ambient temperature. Forworking up it is diluted with water and extracted with ethyl acetate.The combined organic phases are washed with saturated sodium chloridesolution, dried over magnesium sulphate and evaporated. The residue ischromatographed through a silica gel column with ethyl acetate/methanol(95:5 to 90:1) as eluant.

[1079] Yield: 370 mg (79% of theory)

[1080] R_(f) value: 0.33 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[1081] Mass spectrum (ESI⁻): m/z=544, 546 [M−H]⁻

[1082] The following compound is obtained analogously to Example 15:

[1083] (1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(tert.-butyloxycarbonylamino)-ethyl]-piperidin-4-yloxy}-quinazoline

[1084] R_(f) value: 0.38 (Reversed phase ready-made TLC plate (E.Merck), acetonitrile/water/trifluoroacetic acid=50:50:1)

[1085] Mass spectrum (ESI⁺): m/z=516, 518 [M+H]⁺

EXAMPLE 16

[1086]4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[1087] Prepared by reacting4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(4-nitrophenyloxy)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazolinewith 3-methoxypropylamine at 60° C.

[1088] R_(f) value: 0.33 (silica gel, methylene chloride/methanol/conc.aqueous ammonia=90:10:1)

[1089] Mass spectrum (ESI⁺): m/z=518, 520 [M+H]⁺

[1090] The following compound is obtained analogously to Example 15:

[1091] (1)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[1092] Mass spectrum (ESI⁺): m/z=504, 506 [M+H]⁺

[1093] The following compounds may also be prepared analogously to theforegoing Examples and other methods known from the literature: ExampleNo. Structure (1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

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(19)

(20)

(21)

(22)

(23)

(24)

(25)

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(31)

(32)

(33)

(34)

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(43)

(44)

(45)

(46)

(47)

(48)

(49)

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(53)

(54)

(55)

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(67)

(68)

(69)

(70)

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(80)

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(82)

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(92)

(93)

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(98)

(99)

(100)

(101)

(102)

(103)

(104)

(105)

(106)

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(110)

(111)

(112)

(113)

(114)

(115)

(116)

(117)

(118)

(119)

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(121)

(122)

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(126)

(127)

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(131)

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(137)

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(142)

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(150)

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(153)

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(166)

(167)

(168)

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(173)

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(182)

(183)

(184)

(185)

(186)

EXAMPLE 16

[1094] Coated Tablets Containing 75 mg of Active Substance tablet corecontains: active substance 75.0 mg calcium phosphate 93.0 mg corn starch35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropylmethylcellulose 15.0mg magnesium stearate 1.5 mg 230.0 mg

[1095] Preparation:

[1096] The active substance is mixed with calcium phosphate, cornstarch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half thespecified amount of magnesium stearate. Blanks 13 mm in diameter areproduced in a tablet-making machine and these are then rubbed through ascreen with a mesh size of 1.5 mm using a suitable machine and mixedwith the rest of the magnesium stearate. This granulate is compressed ina tablet-making machine to form tablets of the desired shape. Weight ofcore: 230 mg die:  9 mm, convex

[1097] The tablet cores thus produced are coated with a film consistingessentially of hydroxypropylmethylcellulose. The finished film-coatedtablets are polished with beeswax. Weight of coated tablet: 245 mg.

EXAMPLE 17

[1098] Tablets Containing 100 mg of Active Substance Composition: 1tablet contains: active substance 100.0 mg lactose 80.0 mg corn starch34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg

[1099] Method of Preparation:

[1100] The active substance, lactose and starch are mixed together anduniformly moistened with an aqueous solution of thepolyvinylpyrrolidone. After the moist composition has been screened (2.0mm mesh size) and dried in a rack-type drier at 50° C. it is screenedagain (1.5 mm mesh size) and the lubricant is added. The finishedmixture is compressed to form tablets. Weight of tablet: 220 mgDiameter: 10 mm, biplanar, facetted on both sides and notched on oneside.

EXAMPLE 18

[1101] Tablets Containing 150 mg of Active Substance Composition: 1tablet contains: active substance 50.0 mg powdered lactose 89.0 mg cornstarch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mgmagnesium stearate 1.0 mg 300.0 mg

[1102] Preparation:

[1103] The active substance mixed with lactose, corn starch and silicais moistened with a 20% aqueous polyvinylpyrrolidone solution and passedthrough a screen with a mesh size of 1.5 mm. The granules, dried at 45°C., are passed through the same screen again and mixed with thespecified amount of magnesium stearate. Tablets are pressed from themixture. Weight of tablet: 300 mg die:  10 mm, flat

EXAMPLE 19

[1104] Hard Gelatine Capsules Containing 150 mg of Active Substance 1capsule contains: active substance 50.0 mg corn starch (dried) approx.80.0 mg lactose (powdered) approx. 87.0 mg magnesium stearate 3.0 mgapprox. 420.0 mg

[1105] Preparation:

[1106] The active substance is mixed with the excipients, passed througha screen with a mesh size of 0.75 mm and homogeneously mixed using asuitable apparatus. The finished mixture is packed into size 1 hardgelatine capsules. Capsule filling: approx. 320 mg Capsule shell: size 1hard gelatine capsule.

EXAMPLE 20

[1107] Suppositories Containing 150 mg of Active Substance 1 suppositorycontains: active substance 150.0 mg polyethyleneglycol 1500 550.0 mgpolyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate840.0 mg 2000.0 mg 

[1108] Preparation:

[1109] After the suppository mass has been melted the active substanceis homogeneously distributed therein and the melt is poured into chilledmoulds.

EXAMPLE 21

[1110] Suspension Containing 50 mg of Active Substance 100 ml ofsuspension contain: active substance 1.00 gcarboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05 gpropyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g 70%sorbitol solution 20.00 g flavouring 0.30 g dist. water 100 ml

[1111] Preparation:

[1112] The distilled water is heated to 70° C. The methyl and propylp-hydroxybenzoates together with the glycerol and sodium salt ofcarboxymethylcellulose are dissolved therein with stirring. The solutionis cooled to ambient temperature and the active substance is added andhomogeneously dispersed therein with stirring. After the sugar, thesorbitol solution and the flavouring have been added and dissolved, thesuspension is evacuated with stirring to eliminate air.

[1113] 5 ml of suspension contain 50 mg of active substance.

EXAMPLE 22

[1114] Ampoules Containing 10 mg Active Substance Composition: activesubstance 10.0 mg 0.01 N hydrochloric acid q.s. 2.0 ml double-distilledwater

[1115] Preparation:

[1116] The active substance is dissolved in the necessary amount of 0.01N HCl, made isotonic with common salt, filtered sterile and transferredinto 2 ml ampoules.

EXAMPLE 23

[1117] Ampoules Containing 50 mg of Active Substance Composition: activesubstance 50.0 mg 0.01 N hydrochloric acid q.s. 10.0 ml double-distilledwater

[1118] Preparation:

[1119] The active substance is dissolved in the necessary amount of 0.01N HCl, made isotonic with common salt, filtered sterile and transferredinto 10 ml ampoules.

EXAMPLE 24

[1120] Capsules for Powder Inhalation Containing 5 mg of ActiveSubstance 1 capsule contains: active substance  5.0 mg lactose forinhalation 15.0 mg 20.0 mg

[1121] Preparation:

[1122] The active substance is mixed with lactose for inhalation. Themixture is packed into capsules in a capsule-making machine (weight ofthe empty capsule approx. 50 mg). weight of capsule: 70.0 mg size ofcapsule=  3

EXAMPLE 25

[1123] Inhalable Solution for Hand-Held Nebulisers Containing 2.5 mgActive Substance 1 spray contains: active substance 2.500 mgbenzalkonium chloride 0.001 mg 1 N hydrochloric acid q.s. 15.000 mg ethanol/water (50/50)

[1124] Preparation:

[1125] The active substance and benzalkonium chloride are dissolved inethanol/water (50/50). The pH of the solution is adjusted with 1 Nhydrochloric acid. The resulting solution is filtered and transferredinto suitable containers for use in hand-held nebulisers (cartridges).Contents of the container: 4.5 g

We claim:
 1. A compound comprised of the general formula

wherein R^(a) denotes a hydrogen atom or a C₁₋₄-alkyl group, R^(b)denotes a phenyl or 1-phenylethyl group, wherein the phenyl nucleus issubstituted in each case by the groups R¹ to R³, while R¹ and R², whichmay be identical or different, in each case denote a hydrogen, fluorine,chlorine, bromine or iodine atom, a C₁₋₄-alkyl, hydroxy, C₁₋₄-alkoxy,C₂₋₃-alkenyl or C₂₋₃-alkynyl group, an aryl, aryloxy, arylmethyl orarylmethoxy group, a heteroaryl, heteroaryloxy, heteroarylmethyl orheteroarylmethoxy group, a methyl or methoxy group substituted by 1 to 3fluorine atoms or a cyano, nitro or amino group, and R³ denotes ahydrogen, fluorine, chlorine or bromine atom or a methyl ortrifluoromethyl group, R^(c) denotes a cyclobutyl, cyclopentyl orcyclohexyl group which is substituted in each case by a group R⁴—N—R⁵,while R⁴ denotes a hydrogen atom or a C₁₋₃-alkyl group and R⁵ denotes ahydrogen atom or a C₁₋₃-alkyl group, an aminocarbonyl-C₁₋₃-alkyl,C₁₋₃-alkylaminocarbonyl-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)aminocarbonyl-C₁₋₃-alkyl,pyrrolidin-1-ylcarbonyl-C₁₋₃-alkyl, piperidin-1-ylcarbonyl-C₁₋₃-alkyl,homopiperidin-1-ylcarbonyl-C₁₋₃-alkyl,morpholin-4-ylcarbonyl-C₁₋₃-alkyl,homomorpholin-4-ylcarbonyl-C₁₋₃-alkyl,piperazin-1-ylcarbonyl-C₁₋₃-alkyl,4-C₁₋₃-alkyl-piperazin-1-ylcarbonyl-C₁₋₃-alkyl,homopiperazin-1-ylcarbonyl-C₁₋₃-alkyl or a4-C₁₋₃-alkyl-homopiperazin-1-ylcarbonyl-C₁₋₃-alkyl group, ahydroxy-C₂₋₄-alkyl, C₁₋₃-alkyloxy-C₂₋₄-alkyl,C₁₋₄-alkyloxy-carbonylamino-C₂₋₄-alkyl, amino-C₂₋₄-alkyl,C₁₋₃-alkylamino-C₂₋₄-alkyl, di-(C₁₋₃-alkyl)amino-C₂₋₄-alkyl,C₁₋₃-alkylcarbonylamino-C₂₋₄-alkyl, aminocarbonylamino-C₂₋₄-alkyl,C₁₋₃-alkylaminocarbonylamino-C₂₋₄-alkyl,di-(C₁₋₃-alkyl)amino-carbonylamino-C₂₋₄-alkyl,pyrrolidin-1-ylcarbonylamino-C₂₋₄-alkyl,piperidin-1-ylcarbonylamino-C₂₋₄-alkyl,morpholin-4-ylcarbonylamino-C₂₋₄-alkyl, C₁₋₃-alkylsulphonyl-C₂₋₄-alkylor a C₁₋₃-alkylsulphonylamino-C₂₋₄-alkyl group, a(2-oxo-pyrrolidin-1-yl)-C₂₋₄-alkyl, (2-oxopiperidin-1-yl)-C₂₋₄-alkyl,(3-oxo-morpholin-4-yl)-C₂₋₄-alkyl, (2-oxo-imidazolidin-1-yl)-C₂₋₄-alkyl,(2-oxo-3-C₁₋₃-alkyl-imidazolidin-1-yl)-C₂₋₄-alkyl,(2-oxo-hexahydropyrimidin-1-yl)-C₂₋₄-alkyl or a(2-oxo-3-C₁₋₃-alkyl-hexahydropyrimidin-1-yl)-C₂₋₄-alkyl group, aC₁₋₄-alkylsulphonyl, chloro-C₁₋₄-alkylsulphonyl,bromo-C₁₋₄-alkylsulphonyl, amino-C₁₋₄-alkylsulphonyl,C₁₋₃-alkylamino-C₁₋₄-alkylsulphonyl,di-(C₁₋₃-alkyl)amino-C₁₋₄-alkylsulphonyl,(pyrrolidin-1-yl)-C₁₋₄-alkylsulphonyl,(piperidin-1-yl)-C₁₋₄-alkylsulphonyl,(homopiperidin-1-yl)-C₁₋₄-alkylsulphonyl,(morpholin-4-yl)-C₁₋₄-alkylsulphonyl,(homomorpholin-4-yl)-C₁₋₄-alkylsulphonyl,(piperazin-1-yl)-C₁₋₄-alkylsulphonyl,(4-C₁₋₃-alkyl-piperazin-1-yl)-C₁₋₄-alkylsulphonyl,(homopiperazin-1-yl)-C₁₋₄-alkylsulphonyl or a(4-C₁₋₃-alkyl-homopiperazin-1-yl)-C₁₋₄-alkylsulphonyl group, aC₁₋₄-alkyloxycarbonyl group, a formyl, C₁₋₄-alkyl-carbonyl,C₁₋₃-alkyloxy-C₁₋₄-alkyl-carbonyl, tetrahydrofuranylcarbonyl,tetrahydropyranylcarbonyl, amino-C₁₋₄-alkyl-carbonyl,C₁₋₃-alkylamino-C₁₋₄-alkyl-carbonyl,di-(C₁₋₃-alkyl)amino-C₁₋₄-alkyl-carbonyl,pyrrolidin-1-yl-C₁₋₄-alkyl-carbonyl, piperidin-1-yl-C₁₋₄-alkyl-carbonyl,(homopiperidin-1-yl)-C₁₋₄-alkyl-carbonyl,morpholin-4-yl-C₁₋₄-alkyl-carbonyl,(homomorpholin-4-yl)-C₁₋₄-alkyl-carbonyl,(piperazin-1-yl)-C₁₋₄-alkyl-carbonyl,(4-C₁₋₃-alkyl-piperazin-1-yl)-C₁₋₄-alkyl-carbonyl,(homo-piperazin-1-yl)-C₁₋₄-alkyl-carbonyl,(4-C₁₋₃-alkyl-homopiperazin-1-yl)-C₁₋₄-alkyl-carbonyl or aC₁₋₃-alkylsulphonyl-C₁₋₄-alkyl-carbonyl group, a cyano, aminocarbonyl,C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)amino-carbonyl,(C₁₋₃-alkyloxy-C₂₋₄-alkyl)aminocarbonyl,N-(C₁₋₃-alkyl)-N-(C₁₋₃-alkyloxy-C₂₋₄-alkyl)aminocarbonyl,arylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,homopiperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl,3-oxa-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl, 8-oxa-3-aza-[3.2.1]oct-3-ylcarbonyl, piperazin-1-ylcarbonyl,4-C₁₋₃-alkyl-piperazin-1-ylcarbonyl, homopiperazin-1-ylcarbonyl,4-C₁₋₃-alkyl-homopiperazin-1-ylcarbonyl, aminosulphonyl,C₁₋₃-alkyl-aminosulphonyl, di-(C₁₋₃-alkyl)amino-sulphonyl,pyrrolidin-1-yl-sulphonyl, piperidin-1-ylsulphonyl,homopiperidin-1-ylsulphonyl, morpholin-4-ylsulphonyl,homomorpholin-4-ylsulphonyl, piperazin-1-ylsulphonyl,4-C₁₋₃-alkyl-piperazin-1-ylsulphonyl, homopiperazin-1-ylsulphonyl or a4-C₁₋₃-alkyl-homopiperazin-1-ylsulphonyl group, a cyclobutyl,cyclopentyl or cyclohexyl group which is substituted in each case by agroup R⁶, where R⁶ denotes a 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl,3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl,2-oxo-3-C₁₋₃-alkyl-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl or a2-oxo-3-C₁₋₃-alkyl-hexahydropyrimidin-1-yl group, an azetidin-3-yl groupwhich is substituted in the 1 position by the group R⁵, while R⁵ is ashereinbefore defined, a pyrrolidin-3-yl group which is substituted inthe 1 position by the group R⁵, while R⁵ is as hereinbefore defined, apiperidin-3-yl group which is substituted in the 1 position by the groupR⁵, while R⁵ is as hereinbefore defined, a piperidin-4-yl group which issubstituted in the 1 position by the group R⁵, while R⁵ is ashereinbefore defined, or a tetrahydrofuran-3-yl, tetrahydropyran-3-yl ortetrahydropyran-4-yl group, R^(d) denotes a hydrogen atom or a fluorine,chlorine or bromine atom, a hydroxy group, a C₁₋₄-alkyloxy group, amethoxy group substituted by 1 to 3 fluorine atoms, an ethyloxy groupsubstituted by 1 to 5 fluorine atoms, a C₂₋₄-alkyloxy group which issubstituted by a group R⁶ or R⁷, while R⁶ is as hereinbefore defined andR⁷ denotes a hydroxy, C₁₋₃-alkyloxy, C₃₋₆-cycloalkyloxy, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino, bis-(2-methoxyethyl)-amino,pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl,homomorpholin-4-yl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl,3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl,piperazin-1-yl, 4-C₁₋₃-alkyl-piperazin-1-yl, homopiperazin-1-yl orC₁₋₃-alkyl-homopiperazin-1-yl group, or a formylamino,C₁₋₄-alkylcarbonylamino, C₁₋₃-alkyloxy-C₁₋₃-alkyl-carbonylamino,C₁₋₄-alkyloxycarbonylamino, aminocarbonylamino,C₁₋₃-alkylaminocarbonylamino, di-(C₁₋₃-alkyl)aminocarbonylamino,pyrrolidin-1-ylcarbonylamino, piperidin-1-ylcarbonylamino,piperazin-1-ylcarbonylamino, 4-C₁₋₃-alkyl-piperazin-1-ylcarbonylamino,morpholin-4-ylcarbonylamino or a C₁₋₄-alkylsulphonylamino group, aC₃₋₇-cycloalkyloxy or C₃₋₇-cycloalkyl-C₁₋₄-alkyloxy group, atetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy ortetrahydropyran-4-yloxy group, a tetrahydrofuranyl-C₁₋₄-alkyloxy ortetrahydropyranyl-C₁₋₄-alkyloxy group, a C₁₋₄-alkoxy group which issubstituted by a pyrrolidinyl, piperidinyl or homopiperidinyl groupsubstituted in the 1 position by the group R⁸, while R⁸ denotes ahydrogen atom or a C₁₋₃-alkyl group, or a C₁₋₄-alkoxy group which issubstituted by a morpholinyl group substituted in the 4 position by thegroup R⁸, while R⁸ is as hereinbefore defined, and X denotes a methynegroup substituted by a cyano group or a nitrogen atom, and by the arylgroups mentioned in the definition of the above groups is meant in eachcase a phenyl group which is mono- or disubstituted by R⁹, while thesubstituents may be identical or different and R⁹ denotes a hydrogenatom, a fluorine, chlorine, bromine or iodine atom or a C₁₋₃-alkyl,hydroxy, C₁₋₃-alkyloxy, difluoromethyl, trifluoromethyl,difluoromethoxy, trifluoromethoxy or cyano group, by the heteroarylgroups mentioned in the definition of the above groups is meant apyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group, while saidheteroaryl groups are each mono- or disubstituted by the group R⁹, whilethe substituents may be identical or different and R⁹ is as hereinbeforedefined, and said pyrrolidinyl, piperidinyl, piperazinyl and morpholinylgroups may be substituted in each case by one or two C₁₋₃-alkyl groups,and unless otherwise stated, said alkyl groups may be straight-chainedor branched, with the proviso that the compound4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazolineis excluded, their tautomers, their stereoisomers, their mixtures andtheir salts.
 2. A bicyclic heterocyclic group of general formula Iaccording to claim 1, wherein R^(a) denotes a hydrogen atom, R^(b)denotes a phenyl group substituted by the groups R¹ to R³, while R¹denotes a hydrogen, fluorine, chlorine or bromine atom, a methyl,trifluoromethyl or ethynyl group, a phenyloxy or phenylmethoxy group,while the phenyl moiety of the abovementioned groups is optionallysubstituted by a fluorine or chlorine atom, or a pyridyloxy orpyridinylmethoxy group, while the pyridinyl moiety of the abovementionedgroups is optionally substituted by a methyl or trifluoromethyl group,R² denotes a hydrogen, fluorine or chlorine atom or a methyl group andR³ denotes a hydrogen atom, R^(c) denotes a cyclopentyl group which issubstituted in the 3 position by a group R⁴—N—R⁵, while R⁴ denotes ahydrogen atom or a C₁₋₃-alkyl group and R⁵ denotes a hydrogen atom or aC₁₋₃-alkyl group, an aminocarbonyl-C₁₋₃-alkyl,C₁₋₃-alkylaminocarbonyl-C₁₋₃-alkyl,di-(C₁₋₃-alkyl)aminocarbonyl-C₁₋₃-alkyl,pyrrolidin-1-ylcarbonyl-C₁₋₃-alkyl, piperidin-1-ylcarbonyl-C₁₋₃-alkyl,piperazin-1-ylcarbonyl-C₁₋₃-alkyl,4-C₁₋₃-alkyl-piperazin-1-yl-carbonyl-C₁₋₃-alkyl ormorpholin-4-ylcarbonyl-C₁₋₃-alkyl group, a hydroxy-C₂₋₄-alkyl,C₁₋₃-alkyloxy-C₂₋₄-alkyl, C₁₋₄-alkyloxy-carbonylamino-C₂₋₄-alkyl,amino-C₂₋₄-alkyl, C₁₋₃-alkylamino-C₂₋₄-alkyl,di-(C₁₋₃-alkyl)amino-C₂₋₄-alkyl, C₁₋₃-alkylcarbonylamino-C₂₋₄-alkyl,aminocarbonylamino-C₂₋₄-alkyl, C₁₋₃-alkylaminocarbonylamino-C₂₋₄-alkyl,di-(C₁₋₃-alkyl)amino-carbonylamino-C₂₋₄-alkyl,morpholin-4-ylcarbonylamino-C₂₋₄-alkyl, C₁₋₃-alkylsulphonyl-C₂₋₄-alkylor C₁₋₃-alkylsulphonylamino-C₂₋₄-alkyl group, a(2-oxo-pyrrolidin-1-yl)-C₂₋₄-alkyl, (2-oxopiperidin-1-yl)-C₂₋₄-alkyl,(3-oxo-morpholin-4-yl)-C₂₋₄-alkyl, (2-oxo-imidazolidin-1-yl)-C₂₋₄-alkyl,(2-oxo-3-methyl-imidazolidin-1-yl)-C₂₋₄-alkyl,(2-oxo-hexahydropyrimidin-1-yl)-C₂₋₄-alkyl or(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-C₂₋₄-alkyl group, aC₁₋₃-alkylsulphonyl, chloro-C₂₋₄-alkylsulphonyl,bromo-C₂₋₄-alkylsulphonyl, amino-C₂₋₄-alkylsulphonyl,C₁₋₃-alkylamino-C₂₋₄-alkylsulphonyl,di-(C₁₋₃-alkyl)amino-C₂₋₄-alkylsulphonyl,(pyrrolidin-1-yl)-C₂₋₄-alkylsulphonyl,(piperidin-1-yl)-C₂₋₄-alkylsulphonyl or(morpholin-4-yl)-C₂₋₄-alkylsulphonyl group, a C₁₋₄-alkyloxy-carbonylgroup, a formyl, C₁₋₃-alkyl-carbonyl, C₁₋₃-alkyloxy-C₁₋₃-alkyl-carbonyl,tetrahydrofuranylcarbonyl, tetrahydropyranylcarbonyl,amino-C₁₋₃-alkyl-carbonyl, C₁₋₃-alkylamino-C₁₋₃-alkyl-carbonyl,di-(C₁₋₃-alkyl)amino-C₁₋₃-alkyl-carbonyl,pyrrolidin-1-yl-C₁₋₃-alkyl-carbonyl, piperidin-1-yl-C₁₋₃-alkyl-carbonyl,piperazin-1-yl-C₁₋₃-alkyl-carbonyl,4-C₁₋₃-alkyl-piperazin-1-yl-C₁₋₃-alkyl-carbonyl,morpholin-4-yl-C₁₋₃-alkyl-carbonyl or aC₁₋₃-alkylsulphonyl-C₁₋₃-alkyl-carbonyl group, a cyano, aminocarbonyl,C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)amino-carbonyl,(C₁₋₃-alkyloxy-C₂₋₄-alkyl)aminocarbonyl,N-(C₁₋₃-alkyl)-N-(C₁₋₃-alkyloxy-C₂₋₄-alkyl)aminocarbonyl,phenylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,morpholin-4-ylcarbonyl, C₁₋₃-alkyl-morpholin-4-ylcarbonyl,di-(C₁₋₃-alkyl)morpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl,2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl,3-oxa-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl,8-oxa-3-aza-bicyclo[3.2.1]oct-3-ylcarbonyl, piperazin-1-ylcarbonyl,4-(C₁₋₃-alkyl)-piperazin-1-ylcarbonyl, aminosulphonyl,C₁₋₃-alkyl-aminosulphonyl, di-(C₁₋₃-alkyl)amino-sulphonyl,pyrrolidin-1-yl-sulphonyl, piperidin-1-ylsulphonyl or amorpholin-4-ylsulphonyl group, or a cyclopentyl group which issubstituted in the 3 position by a group R⁶, while R⁶ denotes a2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxo-morpholin-4-yl,2-oxo-imidazolidin-1-yl, 2-oxo-3-methyl-imidazolidin-1-yl,2-oxo-hexahydropyrimidin-1-yl or a2-oxo-3-methyl-hexahydropyrimidin-1-yl group, a cyclohexyl group whichis substituted in the 3 position or in the 4 position by a groupR⁴—N—R⁵, while R⁴ and R⁵ are as hereinbefore defined, a cyclohexyl groupwhich is substituted in the 3 position or in the 4 position by a groupR⁶, while R⁶ is as hereinbefore defined, a pyrrolidin-3-yl group whichis substituted in the 1 position by the group R⁵, while R⁵ is ashereinbefore defined, a piperidin-3-yl group which is substituted in the1 position by the group R⁵, while R⁵ is as hereinbefore defined, apiperidin-4-yl group which is substituted in the 1 position by the groupR⁵, while R⁵ is as hereinbefore defined, or a tetrahydrofuran-3-yl,tetrahydropyran-3-yl or tetrahydropyran-4-yl group, R^(d) denotes ahydrogen atom, a C₁₋₃-alkyloxy group, a methoxy group which issubstituted by one to three fluorine atoms, an ethyloxy group which issubstituted in the 2 position by a group R⁶ or R⁷, while R⁶ is ashereinbefore defined and R⁷ denotes a hydroxy, C₁₋₃-alkyloxy, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)amino, bis-(2-methoxyethyl)-amino,pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl,2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl,8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, piperazin-1-yl or a4-C₁₋₃-alkyl-piperazin-1-yl group, or a formylamino,C₁₋₄-alkylcarbonylamino, C₁₋₃-alkyloxy-C₁₋₃-alkyl-carbonylamino,C₁₋₄-alkyloxycarbonylamino, aminocarbonylamino,C₁₋₃-alkylaminocarbonylamino, di-(C₁₋₃-alkyl)aminocarbonylamino,pyrrolidin-1-ylcarbonylamino, piperidin-1-ylcarbonylamino,piperazin-1-ylcarbonylamino,4-C₁₋₃-alkyl-piperazin-1-ylcarbonylamino-morpholin-4-ylcarbonylamino ora C₁₋₄-alkylsulphonylamino group, a propyloxy group which is substitutedin the 3 position by a group R⁶ or R⁷, while R⁶ and R⁷ are ashereinbefore defined, or a butyloxy group which is substituted in the 4position by a group R⁶ or R⁷, while R⁶ and R⁷ are as hereinbeforedefined, and X denotes a nitrogen atom, while, unless stated otherwise,said alkyl groups may be straight-chained or branched, their tautomers,their stereoisomers, their mixtures and their salts.
 3. Bicyclicheterocyclic groups of general formula 1 according to claim 1, whereinR^(a) denotes a hydrogen atom, R^(b) denotes a 3-ethynylphenyl,3-bromophenyl, 3,4-difluorophenyl or 3-chloro-4-fluoro-phenyl group, a3-chloro-4-benzyloxy-phenyl, 3-chloro-4-[(3-fluoro-benzyl)oxy]-phenyl,4-(pyridin-3-yloxy)-phenyl, 4-[(6-methyl-pyridin-3-yl)oxy]-phenyl,3-methyl-4-(pyridin-3-yloxy)-phenyl,3-methyl-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl,3-chloro-4-(pyridin-3-yloxy)-phenyl or3-chloro-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl group, R^(c) denotes acyclohexyl group which is substituted in the 3 position or in the 4position by a group R⁴—N—R⁵, while R⁴ denotes a hydrogen atom, a methylor ethyl group and R⁵ denotes a hydrogen atom, a methyl,aminocarbonylmethyl, methylamino-carbonylmethyl,dimethylaminocarbonylmethyl, pyrrolidin-1-ylcarbonylmethyl,piperidin-1-ylcarbonylmethyl, piperazin-1-ylcarbonylmethyl,4-methylpiperazin-1-ylcarbonylmethyl, morpholin-4-ylcarbonylmethyl,2-(morpholin-4-yl-carbonyl)ethyl or 3-(morpholin-4-yl-carbonyl)propylgroup, an ethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl,2-methoxyethyl, 3-methoxypropyl, 2-(butyloxycarbonylamino)-ethyl,2-aminoethyl, 3-aminopropyl, 2-(acetylamino)ethyl,3-(acetylamino)propyl, 2-(ethylcarbonylamino)ethyl,3-(ethylcarbonylamino)propyl, 2-(propylcarbonylamino)ethyl,3-(propylcarbonylamino)propyl, 2-(ethylaminocarbonylamino)ethyl,3-(ethylaminocarbonylamino)propyl, 2-(dimethylaminocarbonylamino)ethyl,3-(dimethylaminocarbonylamino)propyl,2-(morpholin-4-ylcarbonylamino)ethyl,3-(morpholin-4-ylcarbonylamino)propyl, 2-(methylsulphonyl)ethyl,3-(methylsulphonyl)propyl, 2-(methylsulphonyl-amino)ethyl or a3-(methylsulphonylamino)propyl group, a 2-(2-oxo-pyrrolidin-1-yl)ethyl,2-(2-oxopiperidin-1-yl)ethyl, 2-(3-oxo-morpholin-4-yl)ethyl,2-(2-oxo-imidazolidin-1-yl)ethyl,2-(2-oxo-3-methyl-imidazolidin-1-yl)ethyl,2-(2-oxo-hexahydropyrimidin-1-yl)ethyl or a2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)ethyl group, a3-(2-oxo-pyrrolidin-1-yl)propyl, 3-(2-oxopiperidin-1-yl)propyl,3-(3-oxo-morpholin-4-yl)propyl, 3-(2-oxo-imidazolidin-1-yl)propyl,3-(2-oxo-3-methyl-imidazolidin-1-yl)propyl,3-(2-oxo-hexahydropyrimidin-1-yl)propyl or a3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)propyl group, amethylsulphonyl, ethylsulphonyl, 3-chloropropylsulphonyl,2-(morpholin-4-yl)-ethylsulphonyl or a3-(morpholin-4-yl)-propylsulphonyl group, a propyloxycarbonyl orbutyloxycarbonyl group, a formyl, acetyl, ethylcarbonyl, propylcarbonyl,methoxyacetyl, (2-methoxyethyl)carbonyl, (3-methoxypropyl)carbonyl,tetrahydrofuran-2-ylcarbonyl, tetrahydropyran-4-ylcarbonyl, aminoacetyl,methylaminoacetyl, dimethylaminoacetyl, morpholin-4-ylacetyl,[2-(morpholin-4-yl)ethyl]carbonyl, [3-(morpholin-4-yl)propyl]carbonyl ora methylsulphonylacetyl group, a cyano, aminocarbonyl,methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl,diethylaminocarbonyl, propylaminocarbonyl,(2-methoxyethyl)aminocarbonyl,N-methyl-N-(2-methoxyethyl)-aminocarbonyl,(3-methoxypropyl)aminocarbonyl,N-methyl-N-(3-methoxypropyl)-aminocarbonyl, phenylaminocarbonyl,pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,2-methylmorpholin-4-ylcarbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl,homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-[2.2.1]hept-5-ylcarbonyl,3-oxa-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl,8-oxa-3-aza-bicyclo[3.2.1]oct-3-ylcarbonyl,4-methylpiperazin-1-ylcarbonyl, aminosulphonyl, methylaminosulphonyl,dimethylaminosulphonyl or a morpholin-4-ylsulphonyl group, a cyclohexylgroup which is substituted in the 3 position or in the 4 position by agroup R⁶, while R⁶ denotes a 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl,3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl,2-oxo-3-methyl-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl or a2-oxo-3-methyl-hexahydropyrimidin-1-yl group, a pyrrolidin-3-yl groupwhich is substituted in the 1 position by the group R⁵, while R⁵ is ashereinbefore defined, a piperidin-3-yl group which is substituted in the1 position by the group R⁵, while R⁵ is as hereinbefore defined, apiperidin-4-yl group which is substituted in the 1 position by the groupR⁵, while R⁵ is as hereinbefore defined, a tetrahydrofuran-3-yl,tetrahydropyran-3-yl or tetrahydropyran-4-yl group, R^(d) denotes ahydrogen atom, a methoxy, difluoromethoxy or ethyloxy group, an ethyloxygroup which is substituted in the 2 position by a group R⁶ or R⁷, whileR⁶ is as hereinbefore defined and R⁷ denotes a hydroxy, methoxy, ethoxy,amino, dimethylamino, diethylamino, bis-(2-methoxyethyl)-amino,pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl,2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl,8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, piperazin-1-yl,4-methylpiperazin-1-yl or 4-ethylpiperazin-1-yl group, or anacetylamino, ethylcarbonylamino, propylcarbonylamino,butylcarbonylamino, methoxyacetylamino, butyloxycarbonylamino,ethylaminocarbonylamino, dimethylaminocarbonylamino,pyrrolidin-1-ylcarbonylamino, piperidin-1-ylcarbonylamino,morpholin-4-ylcarbonylamino, methylsulphonylamino, ethylsulphonylaminoor butylsulphonylamino group, a propyloxy group which is substituted inthe 3 position by a group R⁶ or R⁷, while R⁶ and R⁷ are as hereinbeforedefined, or a butyloxy group which is substituted in the 4 position by agroup R⁶ or R⁷, while R⁶ and R⁷ are as hereinbefore defined, and Xdenotes a nitrogen atom, while, unless stated otherwise, said alkylgroups may be straight-chained or branched, their tautomers, theirstereoisomers, their mixtures and their salts.
 4. A bicyclicheterocyclic group of general formula I according to claim 1, whereinR^(a) denotes a hydrogen atom, R^(b) denotes a 3-bromophenyl,3,4-difluorophenyl, 3-chloro-4-fluoro-phenyl or a 3-ethynylphenyl group,or a 3-chloro-4-benzyloxy-phenyl,3-chloro-4-[(3-fluorbenzyl)oxy]-phenyl, 4-(pyridin-3-yloxy)-phenyl,4-[(6-methyl-pyridin-3-yl)oxy]-phenyl,3-methyl-4-(pyridin-3-yloxy)-phenyl,3-methyl-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl,3-chloro-4-(pyridin-3-yloxy)-phenyl or3-chloro-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl group, R^(c) denotes acyclohexyl group which is substituted in the 3 position by an amino,acetylamino, tert.-butyloxycarbonylamino or methylsulphonylamino group,a cyclohexyl group which is substituted in the 4 position by an amino,methylamino, ethylamino, dimethylamino, aminocarbonylmethylamino,methylaminocarbonylmethylamino, dimethylaminocarbonylmethylamino,morpholin-4-ylcarbonylmethylamino,[3-(morpholin-4-ylcarbonyl)propyl]amino,[2-(methylsulphonyl)ethyl]amino, [3-(methylsulphonyl)propyl]amino or[2-(methylsulphonylamino)ethyl]amino group, a cyclohexyl group which issubstituted in the 4 position by a [2-(2-oxo-pyrrolidin-1-yl)ethyl]amino, [2-(2-oxopiperidin-1-yl)ethyl]amino,[2-(2-oxo-imidazolidin-1-yl)ethyl]amino,[2-(2-oxo-3-methyl-imidazolidin-1-yl)ethyl]amino,[2-(2-oxo-hexahydropyrimidin-1-yl)ethyl]amino or[2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)ethyl]amino group, acyclohexyl group which is substituted in the 4 position by a[3-(2-oxo-pyrrolidin-1-yl)propyl]amino,[3-(2-oxopiperidin-1-yl)propyl]amino,[3-(2-oxo-imidazolidin-1-yl)propyl]amino,[3-(2-oxo-3-methyl-imidazolidin-1-yl)propyl]amino,[3-(2-oxo-hexahydropyrimidin-1-yl)propyl]amino or[3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)propyl]amino group, acyclohexyl group which is substituted in the 4 position by anacetylamino, N-(acetyl)-methylamino, aminomethylcarbonylamino,methylaminomethylcarbonylamino, dimethylaminomethylcarbonylamino,morpholin-4-ylmethylcarbonylamino, methoxyacetylamino,N-(methoxyacetyl)-methylamino, tetrahydropyran-4-ylcarbonylamino,N-(tetrahydropyran-4-ylcarbonyl)-methylamino,tert.-butyloxycarbonylamino, N-(tert.-butyloxycarbonyl)-methylamino,aminocarbonylamino, methylaminocarbonylamino,N-(ethylaminocarbonyl)-methylamino, dimethylaminocarbonylamino,N-(dimethylaminocarbonyl)-methylamino,N-(piperidin-1-ylcarbonyl)-methylamino, morpholin-4-ylcarbonylamino,N-(morpholin-4-ylcarbonyl)-methylamino orN-(4-methylpiperazin-1-ylcarbonyl)-methylamino group, a cyclohexyl groupwhich is substituted in the 4 position by a 2-oxo-pyrrolidin-1-yl,2-oxopiperidin-1-yl, 3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl,2-oxo-3-methyl-imidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl or a2-oxo-3-methyl-hexahydropyrimidin-1-yl group, a cyclohexyl group whichis substituted in the 4 position by a methylsulphonylamino,N-(methylsulphonyl)-methylamino, ethylsulphonylamino,N-(ethylsulphonyl)-methylamino, dimethylaminosulphonylamino,N-(dimethylaminosulphonyl)-methylamino, morpholin-4-ylsulphonylamino,N-(morpholin-4-ylsulphonyl)-methylamino-3-chloropropylsulphonylamino,[2-(morpholin-4-yl)-ethyl]sulphonylamino or[3-(morpholin-4-yl)-propyl]sulphonylamino-group, a pyrrolidin-3-ylgroup, a pyrrolidin-3-yl group which is substituted in the 1 position bya methyl, acetyl, methoxyacetyl, tert.-butyloxycarbonyl,morpholin-4-ylcarbonyl or methylsulphonyl group, a piperidin-3-yl group,a piperidin-3-yl group which is substituted in the 1 position by amethyl, acetyl, methoxyacetyl, tert.-butyloxycarbonyl,morpholin-4-ylcarbonyl or methylsulphonyl group, a piperidin-4-yl groupwhich is substituted in the 1 position by a methyl, ethyl, propyl,isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 3-methoxypropyl,2-(methylsulphonyl)-ethyl, 3-(methylsulphonyl)-propyl,2-(tert.-butyloxycarbonylamino)-ethyl, 2-aminoethyl,2-(acetylamino)-ethyl, 2-(ethylcarbonylamino)-ethyl,2-(propylcarbonylamino)-ethyl, 2-(ethylaminocarbonylamino)-ethyl,2-(dimethylaminocarbonylamino)-ethyl,2-(morpholin-4-ylcarbonylamino)-ethyl, 3-(acetylamino)-propyl,3-(ethylcarbonylamino)-propyl, 3-(propylcarbonylamino)-propyl,3-(ethylaminocarbonylamino)-propyl,3-(dimethylaminocarbonylamino)-propyl,3-(morpholin-4-ylcarbonylamino)-propyl, 2-(methylsulphonylamino)-ethyl,3-(methylsulphonylamino)-propyl, (aminocarbonyl)methyl,(methylaminocarbonyl)methyl, (dimethylaminocarbonyl)methyl,(pyrrolidin-1-ylcarbonyl)methyl, (morpholin-4-ylcarbonyl)methyl,2-(morpholin-4-ylcarbonyl)-ethyl or 3-(morpholin-4-ylcarbonyl)-propylgroup, a piperidin-4-yl group which is substituted in the 1 position bya 2-(2-oxo-pyrrolidin-1-yl)-ethyl, 2-(2-oxopiperidin-1-yl)-ethyl,2-(3-oxomorpholin-4-yl)-ethyl, 2-(2-oxo-imidazolidin-1-yl)-ethyl,2-(2-oxo-3-methyl-imidazolidin-1-yl)-ethyl,2-(2-oxo-hexahydropyrimidin-1-yl)-ethyl or2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-ethyl group, a piperidin-4-ylgroup which is substituted in the 1 position by a3-(2-oxo-pyrrolidin-1-yl)-propyl, 3-(2-oxopiperidin-1-yl)-propyl,3-(3-oxomorpholin-4-yl)-propyl, 3-(2-oxo-imidazolidin-1-yl)-propyl,3-(2-oxo-3-methyl-imidazolidin-1-yl)-propyl,3-(2-oxo-hexahydropyrimidin-1-yl)-propyl or3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-propyl group, apiperidin-4-yl group which is substituted in the 1 position by a formyl,acetyl, methoxyacetyl, (2-methoxyethyl)carbonyl,(3-methoxypropyl)carbonyl, methylsulphonylacetyl, aminoacetyl,methylaminoacetyl, (dimethylamino)acetyl, (morpholin-4-yl)acetyl,[2-(morpholin-4-yl)-ethyl]carbonyl, [3-(morpholin-4-yl)-propyl]carbonyl,tetrahydrofuran-2-ylcarbonyl or tetrahydropyran-4-ylcarbonyl group, apiperidin-4-yl group which is substituted in the 1 position by a cyano,aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl,(2-methoxyethyl)aminocarbonyl,N-methyl-N-(2-methoxyethyl)-aminocarbonyl,(3-methoxypropyl)aminocarbonyl,N-methyl-N-(3-methoxypropyl)-aminocarbonyl, isopropylaminocarbonyl,phenylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl,pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,2-methylmorpholin-4-ylcarbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl,homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl,3-oxa-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl,8-oxa-3-aza-bicyclo[3.2.1]oct-3-ylcarbonyl,4-methylpiperazin-1-ylcarbonyl, isopropyloxycarbonyl ortert.-butyloxycarbonyl group, a piperidin-4-yl group which issubstituted in the 1 position by a methylsulphonyl, ethylsulphonyl,[2-(morpholin-4-yl)-ethyl]sulphonyl,[3-(morpholin-4-yl)-propyl]sulphonyl, aminosulphonyl,methylaminosulphonyl, dimethylaminosulphonyl or morpholin-4-ylsulphonylgroup, or a tetrahydrofuran-3-yl, tetrahydropyran-3-yl ortetrahydropyran-4-yl group, R^(d) denotes a hydrogen atom, a methoxy,difluoromethoxy or ethyloxy group, a 2-(morpholin-4-yl)ethyloxy,3-(morpholin-4-yl)propyloxy or 4-(morpholin-4-yl)butyloxy group, a3-(dimethylamino)propyloxy, 3-(diethylamino)propyloxy,3-[bis-(2-methoxyethyl)-amino]propyloxy, 3-(piperazin-1-yl)propyloxy,3-(4-methylpiperazin-1-yl)propyloxy or3-(4-ethylpiperazin-1-yl)propyloxy group, a3-(homomorpholin-4-yl)-propyloxy,3-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-propyloxy,3-(3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl)-propyloxy or3-(8-oxa-3-aza-[3.2.1]oct-3-yl)-propyloxy group, a2-(2-oxo-pyrrolidin-1-yl)-ethyloxy, 2-(2-oxopiperidin-1-yl)-ethyloxy,2-(3-oxomorpholin-4-yl)-ethyloxy, 2-(2-oxo-imidazolidin-1-yl)-ethyloxy,2-(2-oxo-3-methyl-imidazolidin-1-yl)-ethyloxy,2-(2-oxo-hexahydropyrimidin-1-yl)-ethyloxy or2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-ethyloxy group, a3-(2-oxo-pyrrolidin-1-yl)-propyloxy, 3-(2-oxopiperidin-1-yl)-propyloxy,3-(3-oxomorpholin-4-yl)-propyloxy,3-(2-oxo-imidazolidin-1-yl)-propyloxy,3-(2-oxo-3-methyl-imidazolidin-1-yl)-propyloxy,3-(2-oxo-hexahydropyrimidin-1-yl)-propyloxy or3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-propyloxy group, a2-(methoxy)-ethyloxy, 2-(tert.-butyloxycarbonylamino)-ethyloxy,2-(amino)-ethyloxy, 2-(acetylamino)-ethyloxy,2-(ethylcarbonylamino)-ethyloxy, 2-(propylcarbonylamino)-ethyloxy,2-(isobutylcarbonylamino)-ethyloxy, 2-(methoxyacetylamino)-ethyloxy,2-(ethylaminocarbonylamino)-ethyloxy,2-(dimethylaminocarbonylamino)-ethyloxy,2-(pyrrolidin-1-ylcarbonylamino)-ethyloxy,2-(piperidin-1-ylcarbonylamino)-ethyloxy,2-(morpholin-4-ylcarbonylamino)-ethyloxy,2-(methylsulphonylamino)-ethyloxy group,2-(ethylsulphonylamino)-ethyloxy or 2-(butylsulphonylamino)-ethyloxygroup, or a 3-(tert.-butyloxycarbonylamino)-propyloxy,3-(amino)-propyloxy, 3-(acetylamino)-propyloxy or3-(methylsulphonylamino)-propyloxy group, and X denotes a nitrogen atom,their tautomers, their stereoisomers, their mixtures and their salts. 5.A bicyclic heterocyclic group of general formula I according to claim 1,wherein R^(a) denotes a hydrogen atom, R^(b) denotes a3-chloro-4-fluoro-phenyl group or a 3-ethynylphenyl group, R^(c) denotesa cyclohexyl group which is substituted in the 3 position by an amino,acetylamino, tert.-butyloxycarbonylamino or methylsulphonylamino group,a cyclohexyl group which is substituted in the 4 position by an amino,methylamino, dimethylamino, acetylamino, N-(acetyl)-methylamino,methoxyacetylamino, N-(methoxyacetyl)-methylamino,tetrahydropyran-4-ylcarbonylamino,N-(tetrahydropyran-4-ylcarbonyl)-methylamino,tert.-butyloxycarbonylamino, N-(tert.-butyloxycarbonyl)-methylamino,N-(ethylaminocarbonyl)-methylamino, dimethylaminocarbonylamino,N-(dimethylaminocarbonyl)-methylamino,N-(piperidin-1-ylcarbonyl)-methylamino, morpholin-4-ylcarbonylamino,N-(morpholin-4-ylcarbonyl)-methylamino,N-(4-methylpiperazin-1-ylcarbonyl)-methylamino, methylsulphonylamino,N-(methylsulphonyl)-methylamino, ethylsulphonylamino,N-(ethylsulphonyl)-methylamino, dimethylaminosulphonylamino,N-(dimethylaminosulphonyl)-methylamino, morpholin-4-ylsulphonylamino,N-(morpholin-4-ylsulphonyl)-methylamino, 3-chloropropylsulphonylamino,or [3-(morpholin-4-yl)-propyl]sulphonylamino group, a pyrrolidin-3-ylgroup, a pyrrolidin-3-yl group which is substituted in the 1 position bya tert.-butyloxycarbonyl or methylsulphonyl group, a piperidin-3-ylgroup, a piperidin-3-yl group which is substituted in the 1 position bya tert.-butyloxycarbonyl or methylsulphonyl group, a piperidin-4-ylgroup, a piperidin-4-yl group which is substituted in the 1 position bya methyl, (aminocarbonyl)methyl, (dimethylaminocarbonyl)methyl,(morpholin-4-ylcarbonyl)methyl, 2-(tert.-butyloxycarbonylamino)ethyl,2-aminoethyl, 2-(acetylamino)ethyl, 2-(methylsulphonylamino)ethyl,cyano, acetyl, methoxyacety-1, (dimethylamino)acetyl,(morpholin-4-yl)acetyl, tetrahydropyran-4-ylcarbonyl,ethylaminocarbonyl, isopropylaminocarbonyl, phenylaminocarbonyl,dimethylaminocarbonyl, diethylaminocarbonyl, pyrrolidin-1-ylcarbonyl,piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl,2-methylmorpholin-4-ylcarbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl,homomorpholin-4-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl,isopropyloxycarbonyl, tert.-butyloxycarbonyl, methylsulphonyl,dimethylaminosulphonyl or morpholin-4-ylsulphonyl group, or atetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-ylgroup, R^(d) denotes a hydrogen atom, a methoxy or ethyloxy group, a2-(morpholin-4-yl)ethyloxy, 3-(morpholin-4-yl)propyloxy or4-(morpholin-4-yl)butyloxy group, a2-(3-methyl-2-oxo-hexahydropyrimidin-1-yl)-ethyloxy group, a2-(methoxy)-ethyloxy, 2-(tert.-butyloxycarbonylamino)-ethyloxy,2-amino-ethyloxy, 2-(acetylamino)-ethyloxy or2-(methylsulphonylamino)-ethyloxy group or a3-(tert.-butyloxycarbonylamino)-propyloxy, 3-amino-propyloxy,3-(acetylamino)-propyloxy or 3-(methylsulphonylamino)-propyloxy group,and X denotes a nitrogen atom, their tautomers, their stereoisomers,their mixtures and their salts.
 6. The following compounds of generalformula I according to claim 1: (a)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-methoxy-quinazoline,(b)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-methoxy-quinazoline,(c)4-[(3-chloro-4-fluoro-phenyl)amino]-6-((R)-tetrahydrofuran-3-yloxy)-7-methoxy-quinazoline,(d)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,(e)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,(f)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline,(g)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,(h)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{[3-(morpholin-4-yl)-propyl]sulphonylamino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,(i)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,(k)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{[3-(morpholin-4-yl)-propyl]sulphonylamino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,(l)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,(m)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,(n)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,(o)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,(p)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)sulphonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,(q)4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,(r)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,(s)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,(t)4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,(u)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline,(v)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazolineand (w)4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,and the salts thereof.
 7. Physiologically acceptable salts of thecompounds according to claim 1 with inorganic or organic acids or bases.8. Pharmaceutical compositions containing a compound according toclaim
 1. 9. Pharmaceutical compostitions containing a compound accordingto claim 7 optionally together with one or more inert carrier and/ordiluents.
 10. A method of treating disease conditions selected from thelist consisting of benign or malignant tumors, diseases of the airwaysand lungs, diseases of the gastrointestinal tract, the bile duct and thegall bladder said method comprising administering to a patient in needof such treatment a pharmaceutically effective amount of a compoundaccording to claim
 1. 11. A method of treatment for the prevention ofdiseases of the airways and lungs, said method comprised ofadministering to a patient a pharmaceutically effective amount of acompound according to claim 1.